Critical Reviews in Clinical Laboratory Sciences

ISSN: 1040-8363 (Print) 1549-781X (Online) Journal homepage: http://www.tandfonline.com/loi/ilab20

Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells Elzbieta Gocek, Anargyros N. Moulas & George P. Studzinski To cite this article: Elzbieta Gocek, Anargyros N. Moulas & George P. Studzinski (2014) Nonreceptor protein tyrosine kinases signaling pathways in normal and cancer cells, Critical Reviews in Clinical Laboratory Sciences, 51:3, 125-137, DOI: 10.3109/10408363.2013.874403 To link to this article: http://dx.doi.org/10.3109/10408363.2013.874403

Published online: 22 Jan 2014.

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Date: 24 October 2017, At: 12:37

http://informahealthcare.com/lab ISSN: 1040-8363 (print), 1549-781X (electronic) Crit Rev Clin Lab Sci, 2014; 51(3): 125–137 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10408363.2013.874403

REVIEW ARTICLE

Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells Downloaded by [UNIVERSITY OF ADELAIDE LIBRARIES] at 12:37 24 October 2017

Elzbieta Gocek1, Anargyros N. Moulas2,3, and George P. Studzinski3 1

Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland, 2Department of Nutrition and Dietetics, Technological Education Institute of Thessaly, Larissa, Greece, and 3Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA Abstract

Keywords

Protein tyrosine kinases (PTKs) are enzymes that transfer phosphate groups to tyrosine residues on protein substrates. Phosphorylation of proteins causes changes in their function and/or enzymatic activity resulting in specific biological responses. There are two classes of PTKs: the transmembrane receptor PTKs and the cytoplasmic non-receptor PTKs (NRTKs). NRTKs are involved in transduction of signals originating from extracellular clues, which often interact with transmembrane receptors. Thus, they are important components of signaling pathways which regulate fundamental cellular functions such as cell differentiation, apoptosis, survival, and proliferation. The activity of NRTKs is tightly regulated, and de-regulation and/or overexpression of NRTKs has been implicated in malignant transformation and carcinogenesis. Research on NRTKs has shed light on the mechanisms of a number of cellular processes including those involved in carcinogenesis. Not surprisingly, several tyrosine kinase inhibitors are in use as treatment for a number of malignancies, and more are under investigation. This review deals with the structure, function, and signaling pathways of nine main families of NRTKs in normal and cancer cells.

Cancer, leukemia, non-receptor tyrosine kinases, signal transduction History Received 11 October 2013 Revised 12 November 2013 Accepted 8 December 2013 Published online 20 January 2014

Abbreviations: c-Abl: Abelson tyrosine kinase; Arg: Abl-related protein; Akt: protein kinase B; Arp 2/3: actin-related proteins 2/3; Blk: B-lymphocyte kinase; Bmx: bone marrow – expressed kinase; Brk: breast cancer kinase (or PTK6); Btk: Bruton’s tyrosine kinase; Cbp/PAG: Csk-binding Protein; Chromosome Ph: Philadelphia chromosome; CML: chronic myeloid leukemia; Crk: Cdc2-related kinase; Csk: C-terminal Src kinase; EGFR: epidermal growth factor receptor; ERKs: extracellular-signal-regulated kinases; Fak: focal adhesion kinase; Fer: Fes-related protein; Fes: feline sarcoma kinase; Flt3: Fms-like tyrosine kinase; Fps: fujinami poultry sarcoma kinase (Fes); Fgr: feline gardner-rasheed kinase; FL: Flt3 ligand; Frk: Fyn-related kinase; Fyn: Fyn kinase; GAB2: Grb2-associated-binding Protein 2; GPCR: G-protein-coupled receptor; Grb2: growth factor receptor-bound protein 2; Hck: hemopoietic cell kinase; IGF-1: insulin-like growth factor 1; IRS-1: insulin receptor substrate 1; Jaks: janus kinases family; Jnk: c-Jun N-terminal kinase; Itk: inducible T-cell kinase; Lck: lymphocyte-specific protein tyrosine kinase; Lyn: Lck/Yesrelated novel tyrosine kinase; Matk: megakaryocyte-associated tyrosine kinase; Mapks: mitogen-activated protein kinases; MEKs: mitogen-activated protein kinase kinases; Mkk 4/7: mitogen-activated protein kinase kinase 4/7; mTOR: mammalian target of rapamycin; Nck: noncatalytic region of tyrosine kinase adaptor protein 1; Nox: Rac/NADPH oxidase; NRTKs: nonreceptor protein tyrosine kinases; Pax: paxillin; PDK1: 30 -phosphoinositide-dependent kinase; PI3K: phosphatidylinositol-3-kinase; Pim-1/2: proto-oncogene serine/threonine-protein; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; Pkc: protein kinase C; PTKs: protein tyrosine kinases; PTK6: protein tyrosine kinase 6 (also known as Brk); Pyk2: pyruvate kinase 2 (also known as Raftk); Rac: subfamily of the Rho family of GTPases; Raftk: related adhesion focal tyrosine kinase (also known as Pyk2); Sapk: stress-activated protein kinase; SH1: Src homology 1 domain; SH2: Src homology 2 domain; SH3: Src homology 3 domain; SHC: Src-homology-2 protein; SOS 1: son of sevenless homolog 1 protein; Srm/SRMS: Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites; Stat 1/3: signal transducer and activator Referees: Dr. Shile Huang, Biochemistry and Molecular Biology, Luisiana State University, USA; Dr. Geoffrey Brown, School of Immunity and Infection, University of Birmingham, UK; Dr. Zbigniew Darzynkiewicz, Brander Cancer Research Institute, New York Medical College, USA. Address for correspondence: George P. Studzinski, M.D., Ph.D., Pathology and Laboratory Medicine, MSB, Room C-543, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA. Tel: 973-972-5869. Fax: 973-972-7293. E-mail: [email protected]

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of transcription 1/3; Stat 3: signal transducer and activator of transcription 3; Stats: signal transducers and activators of transcription; Syk: spleen tyrosine kinase; Tec: tyrosine kinase expressed in hepatocellular carcinoma; Tnk1: tyrosine kinase, non-receptor-1; Txk: Txk kinase; Tyk 2: tyrosine kinase 2; Wave 1/2: Wiskott-Aldrich Syndrome family protein ½; Yes: yamaguchi sarcoma oncogene kinase; Yrk: Yes-related kinase; Zap70: zeta-chain-associated protein kinase

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Introduction Protein tyrosine kinases (PTKs) catalyze the transfer of the g phosphate of ATP to tyrosine residues on protein substrates. Phosphorylation of tyrosine residues modulates enzymatic activity and creates binding sites for the recruitment of downstream signaling proteins. Two classes of PTKs are present in cells: the transmembrane receptor PTKs and the non-receptor PTKs (NRTKs). Because PTKs are critical components of cellular signaling pathways, their catalytic activity is strictly regulated1. PTKs play an important role in the control of the most fundamental cellular processes including signaling of changes in the cell migration, cell metabolism and survival, as well as cell proliferation and differentiation. Importantly, perturbations of PTK signaling which result in deregulated kinase activity have been implicated in malignant transformation. The human genome contains 518 putative protein kinase genes (1.7% of total genes) and tyrosine kinases account for 17% of these kinase genes2. NRTKs are subdivided into nine main families, based

Figure 1. Domain organization of the major families of NRTKs. NRTKs are subdivided into nine main families, based on their similarities in domain structure. The catalytic (SH1, kinase), p-Tyr binding (SH2), and protein–protein interaction (SH3) domains share a high degree of homology.

on their similarities in domain structure with a high degree of homology in the catalytic Src Homology 1 (SH1), p-Tyr binding Src Homology 2 (SH2), and protein–protein interaction Src Homology 3 (SH3) domains3,4 (Figure 1). A simplified phylogenetic tree of the main NRTKs is shown in Figure 2.

Non-receptor tyrosine kinases Src family The largest group of NRTKs is the Src family5. It is divided into three main subfamilies: Lyn related, Src related, and PTK6/Brk related (Figure 2). The Lyn-related family consists of four members: Lck/Yes-related novel tyrosine kinase (Lyn), hematopoietic cell kinase (Hck), lymphocyte-specific protein tyrosine kinase (Lck), and B lymphocyte kinase (Blk). The second subfamily consists of Src-related kinases, such as feline Gardner-Rasheed kinase (Fgr), the PTK with oncogenic potential Fyn, Yes-related kinase (Yrk), and Yamaguchi

Src family Fak family Csk family Tec family Abl family Syk family Jak family Fes family Ack family Kinase domain

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DNA binding domain

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SH3 domain

Proline-rich region

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Syk ZAP70 Isoforms A and B

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Fes Family

Fer Fes

Figure 2. Families of NRTKs. NRTKs phylogram inferred from amino acid sequences of the kinase domains. Src family is subdivided into three groups: Lyn-related, Src-related and PTK6/Brk (modified from5).

sarcoma oncogene (Yes)6. The third family, the PTK6/Brkrelated, consists of protein tyrosine kinase 6 (PTK6); also known as breast cancer kinase (Brk), Fyn-related kinase (Frk); also known as Rak- and Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (Srms)7 (Figure 2). Yrk was originally detected in chicken8, and no human homolog has been identified so far. Kinases PTK6/Brk, Frk, and Srms are ubiquitously expressed, with high levels in platelets, mast cells, NK cells, and T-cells7. The C-terminal region of the Src family kinases bears an auto-inhibitory phosphorylation site; although, there is a significant variability in the structure of the N-terminal region. The members of this family have a structurally conserved protein domain SH2, which can dock to phosphorylated tyrosine residues in other proteins, and the SH3 domain which auto-regulates the activity of these kinases and also directs binding to specific adaptors including substrates7. Importantly, the SH3 domain binds to the proline-rich region (PRR) – containing proteins. Src kinases participate in a variety of signaling processes, including cell proliferation,

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T- and B-cells activation, cytoskeleton restructuring, cell movement, and endocytosis. Thus, Src kinases regulate a broad spectrum of cellular events such as cell differentiation, apoptosis, survival, and proliferation9–11. Examples of signaling pathways regulated by Src are shown in Figure 3. Several in vivo substrates have been described for Src and include, among others, the PDGF and EGF receptors, the NRTK focal adhesion kinase (Fak), an adaptor protein involved in integrin- and growth factor-mediated signaling (p130Cas), and an actin-binding protein important for the proper formation of cell matrix contact sites (cortactin)12–14. Src de-regulation and overexpression has been implicated in several human cancers, including melanoma, breast, lung, and colon carcinoma15–18. Indeed, Src was the first retroviral oncogene to be identified, and the first proto-oncogene characterized in the vertebrate genome19,20. Elevated expression and activity of Src enhance tumor growth and stimulate its migratory and invasive potential. It may also influence the decision by the cells whether to die or to live. Src also contributes to the various stages of tumor progression, causing enhanced cell multiplication, altering cell–matrix and cell–cell interactions, as well as increasing cell migration, ectopic survival, and growth15. PTK6, also known as breast tumor kinase (Brk), is an intracellular soluble tyrosine kinase with limited homology to the c-Src family. The corresponding mouse protein is the Src-related intestinal kinase (Sik). PTK6, in contrast with other Src kinases, lacks a sequence for myristoylation/ palmitoylation and this allows it to be localized in different sites intracellularly. It has been detected in the cytoplasm and the nuclei in cells of normal human intestine, skin, oral epithelium, breast, and colon tumors21. It contains SH3, SH2, and tyrosine kinase catalytic domains, and it can be autophosphorylated. The substrates of PTK6 include RNAbinding proteins (Sam68, SLM-1, SLM-2, and PSF), signal transducers and activators of transcription (Stat) factors (Stat3 and Stat5a/b), and several signaling molecules21,22. PTK6 exemplifies the diverse functions and properties of NRTKs. Its major biological function in normal tissues is growth regulation, induction of cellular differentiation, and apoptosis22. However, in malignant cells, it promotes oncogenic signaling and can induce proliferation, survival, migration, and invasion21,22. It is expressed mainly in differentiated epithelial cells in the gastrointestinal tract and the skin, and also in the prostate and lymphocytes. Although it is not expressed in normal mammary gland and ovary, it is overexpressed in breast and ovarian tumors, and in several other cancers including melanoma, lymphoma, prostate, lung, and colon cancers21,23. However, it was reported that PTK6 is down-regulated in human esophageal squamous cell carcinoma via epigenetic modification at the PTK6 locus, and that reduced levels of PTK6 promote growth of xenograft tumors in mice24. Additionally, low expression of PTK6 was associated with poor prognosis in laryngeal squamous cell carcinoma25. PTK6 is localized mainly in the nucleus, but in tumors it can be mislocalized. PTK6 nuclear localization was found in biopsies from well-differentiated prostate tumors but not in poorly differentiated tumors and in the PC3 prostate cancer cell line that forms aggressive tumors, suggesting that decreased nuclear localization and activity of BRK in prostate

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Src

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Figure 3. Examples of signaling pathways regulated by Src. Src kinases regulate a broad spectrum of cellular events such as cell growth, differentiation, apoptosis, survival, and proliferation. These include the Ras/Raf/MEKs/ERKs pathways; the PI3K/Akt/mTOR pathway; and the STAT3 pathway that regulates the expression of c-Myc and Cyclin D1. Abbreviations: STAT3, Signal Transducer and Activator of Transcription 3; PI3K, Phosphatidylinositol-3-Kinase; mTOR, Mammalian Target of Rapamycin; Rac, subfamily of the Rho family of GTPases; MEKs, mitogen-activated protein kinase kinases; ERKs, extracellular-signal-regulated kinases; PDK1, 30 -phosphoinositide-dependent kinase; Akt, protein kinase B.

glands is associated with poor differentiation26. Thus, it is possible that the functions of PTK6 differ based on intracellular localization, tissue, type of cells, and malignancy. The Fyn-related kinase, Frk or RAK, another member of the PTK6 family, is expressed in the epithelial cells of the kidney and liver, and in breast and colon cancer cell lines. In contrast to PTK6, Frk is expressed in normal mammary gland but its expression is lost in some breast tumors27. Loss of Frk expression in some breast cancer cell lines reduces the expression of phosphatase and tensin homolog (PTEN), which is a tumor suppressor often mutated in cancers, antagonizes PI3K and prevents PIP3-mediated activation of AKT28,29. In contrast, Frk has been found to be upregulated in samples from hepatocellular carcinoma30. SRMS, the third member of the PTK6 family of kinases, is also overexpressed in breast tumor cells, and its distinct N-terminal region regulates the enzymatic activity of the protein31.

Csk family: C-terminal Src kinase (Csk) and Csk homologous kinase Csk serves as an indispensable negative regulator of the Src family tyrosine kinases (SFKs). Csk specifically phosphorylates the negative regulatory site of SFKs, and thereby suppresses their oncogenic potential37,38. Csk is primarily regulated through its SH2 domain, which is required for membrane translocation of Csk via binding to scaffold proteins such as Cbp/PAG1, caveolin-1, paxillin, or insulin receptor substrate 1 (IRS-1) (Figure 5)39–41. The binding of scaffolds to the SH2 domain can also upregulate Csk kinase activity. Perturbations of the regulatory system consisting of Csk, or its scaffold proteins, and certain tyrosine phosphatases may explain the upregulation of SFKs frequently observed in human cancers, such as non-small lung, colorectal, or hepatocellular carcinomas42–46. Tec family

Fak family This family is classified as a focal adhesion kinase family and consists of two kinases: proline-rich NRTKs – Fak (Focal adhesion kinase) and related adhesion focal tyrosine kinase (Raftk, also known as Pyk2). The molecular mass of both kinases is between 110 and 125 kDa and they are closely related in their structure32. These kinases do not contain SH2 and SH3 domains. Fak is widely expressed in almost all tissues, while Raftk/Pyk2 is expressed mainly in the central nervous system and in hematopoietic cells. Fak is localized to focal adhesion sites in adherent cells, RAFPTK/Pyk2 is mainly diffused throughout the cytoplasm and is concentrated in the perinuclear region33. Fak and Raftk/Pyk2 signaling was studied in various cell types upon exposure to several stimuli, such as hormones, growth factors, integrins, and cytokines34–36. Fak and Raftk/Pyk2 signaling interactions are summarized in Figure 4.

Tec family kinases (TFKs) constitute the second largest family of mammalian NRTKs and comprise five members: Bruton’s tyrosine kinase (Btk), inducible T-cell kinase (Itk), Tec (tyrosine kinase expressed in hepatocellular carcinoma), bone marrow – expressed kinase (Bmx); also known as epithelial and endothelial tyrosine kinase (Etk) and Txk; also known as resting lymphocyte kinase (Rlk). The presence of a distinct proline-rich region and a pleckstrin homology domain distinguish TFKs from the other NRTKs (Figure 1)47. The phenotypes of loss-of-function mutations in mammals mainly affect the hematopoietic system48 with the exception of Etk/Bmx and Tec which also affect endothelial cells and the liver, respectively49. Hematopoietic cells, such as mast cells, T cells, or B cell lymphoma, lacking Btk exhibit defective signaling from the B-cell receptor with abnormal activation of PLCg and decreased Ca2+ mobilization. Tec kinase is specifically expressed in the liver and the kidney.

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Migraon

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Figure 4. Signaling cascades downstream of Fak and Raftk/Pyk2. Tyrosine phosphorylation of Fak or Raftk/Pyk2 activated by integrins or other external stimuli results in signaling by multiple intracellular pathways. Two pathways downstream of Fak have been described which promote cell migration. The first one occurs through Src-mediated activation of p130Cas and Crk/Nck, the second one is mediated by PI3K. Fak prevents apoptosis, probably through PI3K and Akt and as well as by Raftk/Pyk2, promotes cell spreading through Src-mediated phosphorylation of Pax, as does Raftk/ Pyk2. The major event that regulates cell proliferation involves the promotion of Grb2 association with Shc resulting in activation of MAPKs/ERKs pathways. Transcriptional activation of AP-1 occurs through Jnk/Sapk signaling pathway downstream of Raftk/Pyk2. Abbreviations: PI3K, phosphatidylinositol-3-kinase; Pax, paxillin; Sapk, stress-activated protein kinase; Grb2, growth factor receptor 2; MAPKs, mitogen-activated protein kinase; Jnk, c-Jun N-terminal kinase; Akt, protein kinase B; Crk, Cdc2-related kinase; Nck, non-catalytic region of tyrosine kinase adaptor protein 1.

Insulin Receptor Integrin Cbp/PAG

GPCR Caveolin-1

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Figure 5. Interactions of Csk with its scaffolds. Several scaffolding proteins, such as Cbp/PAG, Caveolin-1, paxillin, IRS-1, GPCR have been identified as anchors for Csk. The binding of scaffolds to the SH2 domain of Csk can also activate enzymatic activity of Csk. Csk kinase domain binds to bg subunit of trimeric G-proteins after stimulation of GPCR and supports reorganization of the actin cytoskeleton. Abbreviations: Cbp/PAG, Csk-binding protein; Pax, paxillin; IRS-1, insulin receptor substrate 1; GPCR, G-protein-coupled receptor.

Evidence suggests that it is involved in hepatocyte proliferation and liver regeneration through the Ras-Mapk pathway, and acts between MEK1 and ERK50. Bmx is expressed in arterial endothelium, in certain hematopoietic and epithelial cells, as well as in several types of cancers. Bmx regulates

ischemia-mediated angiogenesis and lymphangiogenesis, and it has been suggested that it also contributes to tumor angiogenesis and growth51. TFKs were best studied in lymphocytes and mast cells, and are critical for the full activation of phospholipase-C g

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(PLC-g) and Ca2+ mobilization downstream of antigen receptors52. Their impact on cellular physiology suggests that Tec kinases help regulate multiple cellular processes beyond Ca2+ mobilization53. It is known that TFKs are activated downstream of many cell-surface receptors, including RTKs, cytokine receptors, antigen receptors, integrins, and G-protein-coupled receptors. Available evidence suggests that the Tec kinases influence a wide range of signaling pathways controlling actin reorganization, transcriptional regulation, cell adhesion and migration, or apoptosis (Figure 6A). Tec kinase is activated in a two-step process. The first one is translocation of Tec to the cell membrane triggered by the interaction of the PH domain with phospholipids, such as PIP3, a product of PI3K (Figure 6B). This is important, as PI3K mediates cell survival by activating AKT kinase, which in turn blocks apoptosis by inactivating pro-apoptotic proteins such as Bad and caspase 9. The second step is based on the phosphorylation of Tyr in a catalytic domain of Tec by Src

(A)

Integrins/ FAK

GPCR

PIP3 / PI3K RTK

family kinases54. Autophosphorylation of the SH3 domain then takes place (Figure 6B). Abl family Abelson tyrosine kinase (Abl) family includes two members: c-Abl and Arg (Abl-related protein). Both proteins can be localized in cytosol, cell membranes, and the actin cytoskeleton55,56. Additionally, c-Abl is also present in the nucleus57. In normal cells, c-Abl contributes to actin remodeling, cell adhesion and motility, DNA damage response, and microbial pathogen response, as illustrated in Figure 758–60. Deregulation and aberrant expression of c-Abl kinases has been implicated in several types of cancer, such as breast cancer61,62, colon cancer63, and non-small-cell lung cancer64. Phosporylated c-Abl activates oncogenic signaling pathways by activation of ERK5, Rac/Jnk, and Stat 1/3 pathways (Figure 8)61,62,65,66. C-Abl is also known to be important for

TNF Cytokine Angen receptors receptors/ JAK receptors/ SFK

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Downstream signaling Figure 6. Signals transmitted through the TFKs. (A) TFKs are activated by several membrane receptors, such as integrins, GPCR, RTKs, TNF receptor, cytokine receptors, or antigen receptors. After the activation, TFKs are involved in a variety of downstream signaling pathways including adhesion/ migration, actin remodeling, Ca2+ influx, apoptosis or cell survival. (B) Activation of TFKs is a two-step process. At first, PH domain of Tec interacts with phospholipids (eg. PIP3) or with other binding partners (i.e. G-protein subunits or PKC) and Tec translocates to plasma membrane vicinity. Second, a tyrosine residue of catalytic domain of Tec is phosphorylated by Src kinases. Subsequently, a tyrosine residue in the SH3 domain is autophosphorylated (denoted as *) and downstream signaling cascades are activated. Abbreviations: PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PKC, protein kinase C.

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Figure 7. c-Abl signaling cascades in normal cells. In normal cells, c-Abl contributes to the migration and invasion of the cells through F-actin remodeling, and mediates growth factors-induced mitogenesis. C-Abl, after the activation of Src kinases by growth factors such as EGF or PDGF, is phosphorylated by the Src kinases. Then c-Abl phosphorylates and activates WAVE complex for Arp2/3 stimulation and causes F-actin assembly (denoted as "). In parallel, c-Abl activates Rac/Jnk and Nox pathways, expression of c-Myc is then induced and the synthesis of DNA takes place. Abbreviations: Nox, Rac/NADPH oxidase; Wave 1/2, Wiskott-Aldrich syndrome family protein 1/2; Arp 2/3, actin-related proteins 2/3; MKK 4/7, mitogen-activated protein kinase kinase 4/7.

Growth factors (EGF, IGF-1)

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Cancer transformaon and growth

Figure 8. c-Abl signaling cascades in cancer cells. Phosporylated by upstream tyrosine kinases, such as Src kinases, EGFR or IGF-1 receptor, c-Abl activates oncogenic signaling pathways by activation of ERK5, Rac/Jnk, and STAT 1/3 pathways. These cascades are required for cell transformation by Src kinases and neoplastic growth. Abbreviations: EGFR, epidermal growth factor receptor; IGF-1, insulin-like growth factor 1; STAT 1/3, signal transducer and activator of transcription 1/3; Rac, rho family of GTPases.

the genesis of chronic myeloid leukemia (CML), where it forms the oncogenic fusion protein with Bcr after the translocation of a part of chromosome 9 to chromosome 2267 (Figure 9). Several small-molecule inhibitors of Abl have been developed for the treatment of CML, such as Imatinib68,69. This inhibitor targets the ATP-binding pocket

of Abl, blocking its kinase activity (Figure 9). However, Imatinib, also known as Gleevec, is also effective in the treatment of Kit–positive gastrointestinal stromal tumors, showing that this PTK inhibitor can also target some RTKs (such as Kit), the platelet-derived growth factor (PDGF), and stem-cell factor (SCF)70–73. Other, perhaps more specific,

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(A) CHROMOSOME 9

with high baseline NF-kB activity regulate the expression of the anti-apoptotic BCL2A180. Since small-molecule Syk inhibitors are available, Syk may turn out to be an attractive therapeutic target in this subset of lymphomas.

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Figure 9. Bcr/Abl fusion protein and its targeted therapy in CML. (A) Chromosome Ph is the shortened form of chromosome 22 created by the translocation of the long arm of chromosome 9 into chromosome 22. After such translocation, proto-oncogene Abl is transferred from the segment q34 of chromosome 9 to the segment q11 of chromosome 22, where Bcr gene is normally located. Bcr/Abl fusion protein (MW 210 kDa) has increased tyrosine kinase activity in comparison to the normal Abl kinase (MW 145 kDa). (B) Br/Abl fusion protein is typical for CML, and becomes the main aim of its targeted therapy. Several small molecule inhibitors have been developed. Originally, the most effective one turned out to be Imatinib Mesylate. This inhibitor specifically binds to the ATP binding pocket of Bcr/Abl kinase in CML cells. Abbreviations: CML, chronic myeloid leukemia; Chromosome Ph, Philadelphia chromosome.

inhibitors are under development, targeting, for example, phosphorylated Abl in Src/Abl signaling cascade74–76. Syk family Spleen tyrosine kinase (Syk) is a 72-kDa protein tyrosine kinase widely expressed on cells that are involved in the immune system and inflammation, such as B cells, T cells, macrophages, and synovial fibroblasts. Syk is involved in intracellular signaling of the multi-chain immune receptors, including B-cell receptor (BCR), z-chain of T-cell receptor (TCR), FcR, and integrins, which contain the immunereceptor tyrosine-based activation motif (ITAM)77,78. In the signaling by granulocyte colony-stimulating factor receptor (G-CSFR encoded by CSF3R gene), Syk forms a three-component complex with G-CSFR and Lyn. It was reported that this complex forms sequentially, with Srcrelated tyrosine kinase Lyn associated with G-CSFR in the absence of the ligand, but addition of G-CSF induced association with Syk as well, presumably activating signaling by the complex79. It was recently found that distinct Syk/ PI3K-dependent pathways determine the survival of Diffuse Large B-cell Lymphoma (DLBCL) cells, and DLBCL cells

The Janus kinases family (Jaks) consists of four members: Jak1, Jak2, Jak3, and tyrosine kinase-2 (Tyk 2). They all share a similar structure, which is characterized by the presence of two kinase domains, one of which is catalytically inactive (Figure 1)81. Jaks were found to be involved in signaling downstream of the insulin receptor, a number of other receptor tyrosine kinases and certain G-protein-coupled receptors. Several cytoplasmic targets for the Jaks have been identified, but their predominant action was found to be the phosphorylation and activation of the signal transducers and activators of transcription (Stat) factors82. Through the Stats, the Jaks activate gene expression linked to cellular stress, proliferation, and differentiation. In the Jak/ Stat pathways, signals are transmitted from outside the cells (e.g. chemical signals), through the cell membrane, to promoters of the target genes (e.g. p21, Bcl-xl, Myc). Stats are phosphorylated by Jaks in response to cytokines, then dimerize and translocate into the nucleus83–85 (Figure 10). The Jaks are especially important in hematopoiesis, inflammation, and immunity, and aberrant Jak activity has been implicated in a number of disorders including ALL, AML, rheumatoid arthritis, psoriasis, polycythemia vera, and myeloproliferative diseases86. Dysregulation of Jak-Stat signaling AK-Stat is observed in most patients with myeloproliferative neoplasms, and Jak inhibitors have been shown to be efficacious as treatment87. Rearrangements of the Jaks gene that lead to constitutively activated tyrosine kinase activity with oncogenic properties have been involved in the development of leukemia. Jak2 mutations, and translocations result in a variety of chimeric transcripts and in the expression of their resultant fusion proteins, such as PCM1-Jak2 in M2 and M6 subtypes of AML87. Jak2 is also involved in the signaling by growth hormone and leptin. Growth hormone binding to its receptor increases the affinity for Jak2 resulting in complex formation that in turn activates several signaling pathways including the Stat and the MAP kinase (ERK) transduction pathways88,89. Jak2 phosphorylation of leptin receptors is also required for activation of Stat5 and Stat3 signaling90. The Jak/ Stat and Mapk/ERK pathways are thought to be involved in the epigenetic aspects of pathogenesis of hematopoietic malignancies91. Tyk2 deficiency is associated with increased susceptibility to mycobacterial and viral infections, hyper IgE syndrome as well as with allergic asthma. Also, a role of Tyk2 in oncogenesis and tumor progression has been suggested92 and Tyk2 overexpression has been detected in several human breast cancer cell lines, as well as in prostate cancers and squamous cervical carcinomas93. Fes family Feline sarcoma (Fes) also known as Fujinami poultry sarcoma protein (Fps) and its homologous-related protein Fer, are the only two members of a distinct class of NRTKs. Fes signals

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Figure 10. Jak/STAT signaling pathway. Ligand binding to the cytokine receptors induces their dimerization. Jaks bind to the receptors via their SH2 domains, undergo cross-phosphorylation and subsequently phosphorylate STATs. STATs dissociate from their receptors and dimerize via their SH2 domains. They then migrate to nucleus and activate transcription of target genes. Abbreviations: Jaks, Janus kinases family; STATs, signal transducers and activators of transcription.

downstream of several classes of receptors involved in regulation of hematopoietic cell development, survival, migration, inflammatory mediator release, and angiogenesis. Activated Fes is a potent inducer of myeloid differentiation; however, Fes-deficient mice have only subtle derangements in hematopoiesis94. Some studies indicate that Fes kinase plays a role in regulating cytoskeletal rearrangements and inside–out signaling that accompany receptor–ligand, cell–matrix, and cell– cell interactions. While Fer is expressed ubiquitously, Fes expression is restricted to myeloid hematopoietic cells, some neuronal cells, epithelial cells, and vascular endothelial cells. It was found that Src and Fes families play vital roles in the responses of cultured endothelial cells to several proangiogenic factors95. Both Fes and Fer kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. Fes and Fer activation is dependent on Flt3 (Fms-like tyrosine kinase 3). This transmembrane tyrosine receptor kinase is most commonly mutated in AML96. When Flt3 is ligand activated, it dimerizes and is autophosphorylated, initiating signaling cascades that induce cell growth, and inhibiting apoptosis. The oncogenic mutations in Flt3 (internal tandem duplication in the juxtamembrane region or in the catalytic domain, ITD) cause ligand-independent dimerization of the Flt3 and its constitutive activation. Thus, the mutated Flt3 receptor activates downstream signaling pathways, such as PI3-kinase, MAP-kinases ERK1/2 and p38, LYN, and Stat5, leading to the cytokine-independent proliferation97,98 (Figure 11). Mutant Flt3 expression in patients with AML is a poor prognostic factor, and thus, several Flt3 inhibitors are under clinical investigation as treatment for AML patients99,100. Moreover, both Fes and Fer proteins are activated downstream of Flt3 and are critical for Flt3- ITD signaling and for cell proliferation in AML cell lines (i.e. MV4-11, MOLM-13) and primary blasts harboring constitutively active Flt3 mutants. Flt3 co-immunoprecipitated with Fes and Fer in MV4-11 and MOLM-13 AML cell lysates but

not with an isotype-control antibody, indicating that Fes and Fer are part of the Flt3 receptor signaling complex101. Fer is required for cell cycle transitions, whereas Fes seems necessary for cell survival. It was concluded that Fes and Fer kinases mediate essential functions downstream of Flt3-ITD101. Ack family Ack family of NRTKs is unique with regard to the domain composition (Figure 1) and regulatory properties. Human Ack1 (activated Cdc42-associated kinase, also known as Tnk2) is ubiquitously expressed, with the highest level in spleen, thymus, and brain102. This protein is activated by signals that include growth factors and integrin-mediated cell adhesion that promote its phosphorylation. Ack1 overexpression is associated with poor prognosis and metastatic phenotypes in human tumors, such as breast, renal, and prostate cancers103,104. In breast cancer cells, Ack1 acts as a downstream effector of Cdc42 which binds to activated Cdc42 but not to Rho or Rac, and subsequently activates breast cancer anti-estrogen resistance 1 protein (BCAR1, also known as p130Cas)105,106. Ack1 can be activated by EGF and interacts with EGFR via its EGFR-binding domain102. Amplification of the Ack1 gene or its overexpression in primary tumors correlates with poor prognosis, leading to the suggestion that Ack1 can function as an oncogene when overexpressed107. The Ack family also includes Tnk1/Kos1, which is a nonreceptor protein tyrosine kinase implicated in negative regulation of cell growth by a mechanism involving inhibition of Ras activation that requires Tnk1/Kos1’s intrinsic catalytic activity108. Tnk1/Kos1 associates with the Grb2-Sos1 complex and directly phosphorylates tyrosine residue of Grb2, not Sos1. Potentially, this can negatively regulate Grb2-Sos1/GEF complex and lead to the indirect inhibition of Ras and aborting downstream Ras signaling pathways (Figure 12). For this reason, in an interesting contrast to Tnk2/Ack1, Tnk1/ Kos1 is believed to have tumor suppressor activity108.

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Survival and/or proliferation Figure 11. Flt3 signaling pathways. Flt3 ligand binds to Flt3 receptor resulting in the dimerization with conformational changes and autophosphorylation with activation of kinase activity, that in turn activates downstream signaling pathways. In acute myeloid leukemia mutations of the Flt3 gene, with the most common being the internal tandem duplication (ITD) mutation, cause constitutive activation of kinase activity. This results in increased cell survival and/or proliferation growth. Fes and Fer are thought to be a part of the Flt3 signaling complex and are required for ITD signaling (modified from 85). Abbreviations: FL, Flt3 ligand; Fes, fujinami poultry sarcoma; Fer, feline sarcoma; SHC, Src-homology-2 protein; Jaks, janus kinases family; STATs, signal transducers and activators of transcription; GAB2, GRB2-associated-binding protein 2; Pim-1/2, proto-oncogene serine/threonine-protein.

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Downstream signaling Figure 12. Tnk1/Kos1 signaling pathway. Growth factor receptor-mediated Ras activation is regulated by GEFs which catalyze the exchange of GDP for GTP. It is hypothetized that the mechanism by which activated Tnk1/Kos1 inhibits the Ras/GEF activity is uncoupling of the activated Grb2-Sos1/ GEF complex, which indirectly suppresses Ras and aborts downstream signaling from Ras. Abbreviations: Grb 2, growth factor receptor-bound protein 2; SOS 1, son of sevenless homolog 1 protein.

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Conclusions Numerous studies of NRTKs have contributed very significantly to advances in our understanding of molecular biology in general. For instance, studies on Src with its homology regions serve as a tool to identify protein–protein interactions, and have provided a key for our understanding of intracellular signaling109. Also highly notable is the Abl fusion protein which serves as a paradigm for targeted therapy for neoplastic diseases75,110–112. Thus, it is most likely that if further exploration of these protein kinases is accelerated, a rich harvest of discoveries will benefit human health.

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Acknowledgements Experimental work of the authors was supported by the NIH grant 2R01CA044722-23 from the National Cancer Institute (to GPS), and Grant No. 0351/B/P01/2011/40 from National Science Centre (to EG).

Declaration of interest The authors report no conflicts of interest.

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