The
expanding growth hormone/prolactin family
M. Wallis
identical
Introduction A new member of the growth hormone (GH)/prolactin family was characterized in 1984 (Linzer & Nathans, 1984), and named proliferin in recognition of its production by proliferating mouse fibroblasts. Since then there has been a remarkable proliferation of new GH- and prolactin-like proteins in what had seemed to be an old and stable family. Many of these proteins are produced in the placenta, which is now also recognized as a major source of proliferin itself, but a new pituitary hormone has been identified in fish, and possible homology of GH and prolactin with other cytokines is also now apparent. The purpose of this communication is to summarize current knowledge of the new proteins in this family and to assess their relationships to GH and prolactin.
The GH gene
family
in humans
In humans, the gene for GH (hGH-N) occurs as a member of a cluster of five related genes on chromosome 11 (Chen et al. 1989; reviewed by Wallis, 1989). The other genes in this cluster include a 'vari¬ ant' GH gene (hGH-V) that codes for a protein very similar to human (h)GH, and which is now known to be expressed in the placenta (Frankenne et al. 1987; Chen et al. 1989), two genes for human placental lactogen (hPL; also known as human choriomammosomatotrophin, hCS) that code for identical protein sequences (hCS-A/hPL-4 and hCS-B/hPL3), and another PL-like gene (hCS-L/hPL-1) which may not be expressed as protein. hPL was identified in human placenta many years ago and is well char¬ acterized, although its function remains poorly understood. Its amino acid sequence is very similar to that of hGH (about 85% identity); the sequence of hGH resembles that of hPL much more closely than it does those of non-primate GHs, indicating that hPL arose following a duplication of the GH gene that occurred after the separation of the main orders of placental mammals. The hGH-V gene also resembles hGH-N very closely (the proteins are
about 93% of all
residues), probably recent origin by gene dupli¬ reflecting cation. However, the protein coded by the hGH-V gene is probably glycosylated (unlike hGH itself). Its biological properties differ from those of hGH (MacLeod et al. 1991) and its expression in the pla¬ centa but not the anterior pituitary gland suggests a distinct function during human gestation. There is at
an even more
no
evidence for
a
cluster of GH-like genes in the
non-primate mammals that have been studied, and it seems likely that the cluster seen in humans arose during the course of primate evolution by a series of gene duplications. lactogens and related proteins in non-primate mammals The occurrence of placental lactogens in various non-primate mammals has been suspected for many
Placental
characterization, with the clear demonstration that (unlike hPL) they resemble prolactins more than GHs, has only been achieved quite recently. It is now clear that in both ruminants and rodents there are complex sub-families of prolactinlike proteins that are produced in the placenta.
years, but detailed
Ruminants The situation in ruminants is particularly complex. Schuler et al. (1988) reported the amino acid sequence of bovine PL (bPL-Ala), but sequences of at least seven additional prolactin-like proteins from bovine placenta have now been determined, mainly via cDNA cloning (Kessler et al. 1989; Tanaka et al. 1989; Yamakawa et al. 1990; Tanaka et al. 1991). Their nomenclature has recently been revised, and all have been designated either placental lactogens
(PLs)
or
prolactin-related proteins (PRPs) (Schüler
al. 1991). Four were originally termed bovine pro¬ lactin-like proteins (bPLPs) I, II, III and IV (now respectively bPL-Val, bPRP-IV, bPRP-V and bPRP-VI), while the others were termed bovine pro¬ lactin-related cDNAs (bPRCs) I, II and III (now et
respectively bPRP-I, bPRP-II and bPRP-III). On
the basis of sequence similarities, these various pro¬ teins fall into five groups: (1) bPL-Ala and bPLVal (differing only by a single residue); (2) bPRP-I, bPRP-II and bPRP-IV; (3) bPRP-III; (4) bPRP-V; (5) bPRP-VI. The last is very unusual in lackjng the C-terminal disulphide loop that is present in all other members of the GH/prolactin protein family. Each group shows greater sequence similarity to bovine prolactin than to the sequence deduced for the pro¬ lactin of the 'ancestral placental mammal' (a sequence very similar to those of pig and whale prolactins; Wallis, 1981), suggesting that all of the prolactin-like hormones in the bovine placenta originated as a consequence of one or more duplica¬ tions of the prolactin gene that occurred after separa¬ tion of the main orders of placental mammals. Whether a single duplication of the prolactin gene gave rise to the placental hormones (with subsequent duplications of the 'PL/PRP' gene to give the various placental proteins), or whether several duplications of the prolactin gene itself occurred, is not yet clear. It is clear, however, that once the ruminant PL-like genes and proteins arose, their evolution was very rapid the differences between them are much greater than those between most of the mammalian prolactins. This rapid evolution is borne out by the characterization of ovine PL (Colosi et al. 1989), which is clearly homologous with its bovine coun¬ terpart, but differs from it at about 33% of all resi¬ dues (contrasting with 1% of all residues when ovine and bovine prolactins are compared). -
Rodents The prolactin-like proteins found in the rodent pla¬ centa also present a complex picture (reviewed by Southard & Talamantes, 1991). Two PLs (PL-I and PL-11) have been identified from rat, mouse and hamster (Duckworth et al. 1986; Jackson et al. 1986; Colosi et al. 1987; Southard et al. 1989; Robertson et al. 1990) and show considerable sequence similarity, although hamster PL-I I has the unusual feature of an additional disulphide bridge. At least four addi¬ tional prolactin-like proteins are expressed in rat pla¬ centa (rPLP-A, rPLP-B, rPLP-C and rPL-I variant) (Robertson et al. 1990; Deb et al. 1991; Robertson et al. 1991) and two quite different ones in mouse placenta (mPRP and proliferin) (Linzer & Nathans, 1984, 1985). Similarities between any two of these are no greater than similarity to prolactin (except that rPL-I and rPL-I variant show about 85% ident¬ ity). Analysis of the sequences of these various pro¬ teins indicates that although they are clearly prolactin-like, they resemble rat or mouse prolactin less closely than they do the sequence deduced for the 'ancestral placental mammal'. However, rodent
prolactins appear to have been evolving extremely rapidly (Wallis, 1981), and one cannot conclude from the data available whether the rodent PLs (and other rodent prolactin-like placental proteins) arose before or after separation of the main orders of pla¬
cental mammals. There thus appear to be at least three groups of PL-like hormones that have arisen independently in the GH/prolactin family (see Table 1 for summary). Their appearance is obviously associated with the appearance of the placenta during mammalian evolu¬ tion. Presumably, evolutionary development of placentation led to a need for new hormones for the control of fetal growth, fetal—maternal relations and mammary development, and to a new organ able to produce such hormones. Analysis of the sequences available suggests that these PL-like proteins evolved very rapidly once they appeared, contrasting with the slow underlying rate of evolution for GH and prolactin, and in accordance with previous sug¬ gestions that rates of evolution in this family have been very variable (Wallis, 1981). The biological role of these proteins is poorly understood, although observations that the different placental proteins are expressed at different times during the course of pregnancy (e.g. Robertson et al. 1990) suggest that they do have separate and clear-cut roles in the con¬ trol of fetal and/or maternal development. The phy¬ siology and biochemistry of these many new placental proteins will need intensive study if our understanding of their functions is to keep pace with the rate at which they are being discovered.
Somatolactin
prolactin themselves probably arose follow¬ gene duplication which occurred early in the
GH and
ing
a
evolution of vertebrates or chordates; the two have been established as separate hormones in most fish groups as well as in tetrapods. The recent charac¬ terization of a new pituitary protein, named somato¬ lactin, in teleost fish, including flounder (Ono et al. 1990), cod (Rand-Weaver et al. 1991) and salmon (Takayama et al. 1991ft), has provided a new member of the GH/prolactin family which is about equally similar to GH and prolactin, and which may have arisen at about the same time that these two hor¬ mones diverged. As in other groups, teleost GH and prolactin are found in the anterior lobe of the pitu¬ itary gland. Somatolactin was isolated from the inter¬ mediate lobe of this gland, which in teleosts contains two main secretory cell types, one of which produces a melanocyte-stimulating hormone (equivalent to that found in the intermediate lobe of many mam¬ mals) while the other (the PIPAS cell) is rich in glycoprotein and appears to be involved in responses
table
1. Proteins of the
GH/prolactin family Species
GH-like proteins** GH GH variant Human PL hCS-L
GH/prolactin-like proteins Somatolactin Prolactin-like proteins Prolactin Rodent placental proteins PL-I PL-II PL-I variant
Proliferin PRP PLP-A PLP-B
PLP-C Ruminant PL PRP-1 PRP-11
PRP-IV PRP-III PRP-V PRP-VI
placenta] proteins
distribution*
Tissue of
expression
Most vertebrates Human Human (primates?) Human
Anterior pituitary Placenta Placenta Placenta?
Teleost fish
Pituitary (intermediate lobe)
Most vertebrates
Anterior
Mouse, rat Mouse, rat, hamster
Placenta Placenta Placenta
Rat Mouse Mouse Rat Rat Rat
Placenta;
pituitary
some
proliferating
cells
Placenta Placenta Placenta Placenta
Ox, sheep
Placenta Placenta Placenta Placenta Placenta Placenta Placenta
Ox Ox Ox Ox Ox Ox
distribution indicates those groups for which a sequence has been reported. Omission of a species or group from the list does not necessarily indicate that the protein does not occur there. **Variants of GH and prolactin produced by post-transcriptional (e.g. 20 kDa human GH) or post-translational processing are not included. PL, placental lactogen; hCS, human choriomammosomatotrophin; PRP, prolactin-related protein; PLP, prolactinlike protein.
*Species
relating to environmental changes. The main glycoprotein in the PIPAS cell of the flounder is somato¬ lactin, which has now been isolated and characterized, and for which the cDNA has been cloned (Ono et al. 1990). The sequence of this cDNA
indicates that the precursor of somatolactin contains 231 amino acid residues, including a signal sequence of 24 residues. The mature somatolactin thus con¬ tains 207 residues, including a single potential glyco¬ sylation site and seven half-cystine residues. Somatolactin shows sequence similarity with both GHs (24-28% identity) and prolactins (23-26% identity), and a similar degree of similarity to placen¬ tal lactogens and proliferin. Ono et al. (1990) have concluded that it arose as the consequence of a gene duplication that occurred after the separation of GH and prolactin but before the separation of the lines giving rise to teleosts and tetrapods. There is a good deal of evidence that somatolactin plays a role in adaptation of fish to environmental variations, including (depending on the species) dark back¬ ground, acidic pH, low Ca concentration and low osmolarity. It is possible that the hormone may occur quite widely in the vertebrates (Ono et al. 1990), but the evidence for its occurrence in mammals is rather tenuous. In fish, somatolactin
strongly conserved than corresponding GHs (Takayama et al.
sequences appear to be more
those of the
1991a). The
cytokine family
In the past few years, receptors for GH and prolactin have been characterized by cDNA cloning and sequ¬ encing (reviewed by Kelly et al. 1991). They have been shown to have several features in common with the receptors for a number of cytokines (such as erythropoietin, interleukins-2, -3, -4, -5, -6 and -7 and colony-stimulating factors), including some sequence similarity. This strongly suggests that these proteins are related phylogenetically and rep¬ resent a superfamily. The question then arises as to whether the ligands for these receptors may also be related. The tertiary structures of several of these hormones and cytokines have now been determined or predicted, and at this level there are resemblances (though such resemblances are difficult to detect at the level of amino acid sequence, possibly because of divergent evolution). The tertiary structure of GH (Abdel-Meguid et al. 1987) shows a char¬ acteristic four-helical bundle with an unusual and
characteristic arrangement of the a-helices ('up-updown-down'). Four-helical bundles with the same arrangement of a-helices have been reported for interleukin-4 (Redfield et al. 1991) and predicted for erythropoietin, interleukin-6 and granulocyte colony-stimulating factor (reviewed by Bazan, 1990). It seems unlikely that this is a coincidence, and it is at least possible that GH, prolactin and the placental lactogens are members of a larger superfamily of hormones and cytokines which share struc¬ tural features, have similar mechanisms of action (in view of similarities between their receptors) and may have had a common evolutionary origin. This idea may have major implications for the way that we view these important regulatory proteins; the GH/ prolactin family is not only expanding, but is dis¬ covering distant relations which were previously
unsuspected.
REFERENCES
Abdel-Meguid, S. S., Shieh, H.-S., Smith, W. W., Dayringer, H. E., Violand, B. N. & Bentle, L. A. (1987). Proceedings of the National Academy of Sciences of the U.S.A. 84, 6434-6437.
Bazan, J. F. (1990). Immunology Today 11, 350-354. Chen, E. Y., Liao, Y.-C, Smith, D. H., Barrera-Saldana, H. A., Celinas, R. E. & Seeburg, P. H. (1989). Genomics 4, 479-497.
Colosi, P., Talamantes, Molecular
F. &
Endocrinology 1,
Linzer, D. I. H. (1987). 767-776.
Colosi, P., Thordarson, G., Hellmiss, R., Singh, K., Forsyth, I. A., Gluckman, P. & Wood, W. I. (1989). Molecular Endocrinology 3, 1462-1469. Deb, S., Roby, K. F., Faria, T. N., Szpirer, C, Levan, G., Kwok, S. C. M. & Soares, M. J. (1991). Journal of Biological Chemistry 266, 23027-23032. Duckworth, M. L., Kirk, K. L. & Friesen, H. G. (1986). Journal of Biological Chemistry 261, 10871-10878. Frankenne, F., Rentier-Delrue, F., Scippo, M.-L., Martial, J. & Hennen, G. (1987). Journal of Clinical Endocrinology and Metabolism 64, 635-637. Jackson, L. L., Colosi, P., Talamantes, F. & Linzer, D. I. H. (1986). Proceedings of the National Academy of Sciences of the U.S.A. 83, 8496-8500. Kelly, P. A., Djiane, J., Postel-Vinay, M.-C. & Edery, M. (1991). Endocrine Reviews 12, 235-251.
Kessler, M. A., Milosavljevic, M., Zieler, C. G. & Schüler, L. A. (1989). Biochemistry 28, 5154-5161. Linzer, D. I. H. & Nathans, D. (1984). Proceedings of the National Academy of Sciences of the U.S.A. 81, 4255-4259. Linzer, D. I. H. & Nathans, D. (1985). EMBO Journal 4, 1419-1423.
MacLeod, J. N., Worsley, I., Ray, J., Friesen, H. G., Liebhaber, S. A. & Cooke, N. E. (1991). Endocrinology 128, 1298-1302. Ono, M., Takayama, Y., Rand-Weaver, M., Sakata, S., Yasunaga, T., Noso, T. & Kawauchi, H. (1990). Proceedings of the National Academy of Sciences of the U.S.A. 87, 4330-4334. Rand-Weaver, M., Noso, T., Muramoto, K. & Kawauchi, H. (1991). Biochemistry 30, 1509-1515. Redfield, C, Smith, L. J., Boyd, J., Lawrence, G. M. P., Edwards, R. G., Smith, R. A. G. & Dobson, C. M. (1991). Biochemistry 30, 11029-11035. Robertson, M. C, Croze, F., Schroedter, I. C. & Friesen, H. G. (1990). Endocrinology 127, 702-710. Robertson, M. C, Schroedter, I. C. & Friesen, H. G. (1991). Endocrinology 129, 2746-2756. Schuler, L. A., Kessler, M. A., Tanaka, M. & Nakashima, K. (1991). Endocrinology 129, 2057. Schuler, L. A., Shimomura, K., Kessler, M. A., Zieler, C. G. & Bremel, R. D. (1988). Biochemistry 27, 8443 8448. Southard, J. N., Do, L., Smith, W. C. & Talamantes, F. (1989). Molecular Endocrinology 3, 1710 1713. Southard, J. N. & Talamantes, F. (1991). Molecular and Cellular Endocrinology 79, C133-C140. Takayama, Y., Ono, M., Rand-Weaver, M. & Kawauchi, H. (1991a). General and Comparative Endocrinology 83, 366-374.
Takayama, Y., Rand-Weaver, M., Kawauchi, H. & Ono, M. (19916). Molecular Endocrinology 5, 778-786. Tanaka, M., Minoura, H., Ushiro, H. & Nakashima, K. (1991). Biochimica et Biophysica Acta 1088, 385-389. Tanaka, M., Yamakawa, M., Watahiki, M., Yamamoto, M. & Nakashima, K. (1989). Biochimica et Biophysica Acta 1008, 193-197.
Wallis, M. (1981). Journal of Molecular Evolution 17, 10-18. Wallis, M. (1989). Molecular Aspects of Medicine 10, 429-509. Yamakawa, M., Tanaka, M., Koyama, M., Kagesato, Y., Watahiki, M., Yamamoto, M. & Nakashima, K. (1990). Journal of Biological Chemistry 265, 8915-S920.
Biochemistry Laboratory, School of Biological Sciences, University of Sussex, Brighton BN1 9QG, U.K.
expanding growth hormone/prolactin family
M. Wallis
identical
Introduction A new member of the growth hormone (GH)/prolactin family was characterized in 1984 (Linzer & Nathans, 1984), and named proliferin in recognition of its production by proliferating mouse fibroblasts. Since then there has been a remarkable proliferation of new GH- and prolactin-like proteins in what had seemed to be an old and stable family. Many of these proteins are produced in the placenta, which is now also recognized as a major source of proliferin itself, but a new pituitary hormone has been identified in fish, and possible homology of GH and prolactin with other cytokines is also now apparent. The purpose of this communication is to summarize current knowledge of the new proteins in this family and to assess their relationships to GH and prolactin.
The GH gene
family
in humans
In humans, the gene for GH (hGH-N) occurs as a member of a cluster of five related genes on chromosome 11 (Chen et al. 1989; reviewed by Wallis, 1989). The other genes in this cluster include a 'vari¬ ant' GH gene (hGH-V) that codes for a protein very similar to human (h)GH, and which is now known to be expressed in the placenta (Frankenne et al. 1987; Chen et al. 1989), two genes for human placental lactogen (hPL; also known as human choriomammosomatotrophin, hCS) that code for identical protein sequences (hCS-A/hPL-4 and hCS-B/hPL3), and another PL-like gene (hCS-L/hPL-1) which may not be expressed as protein. hPL was identified in human placenta many years ago and is well char¬ acterized, although its function remains poorly understood. Its amino acid sequence is very similar to that of hGH (about 85% identity); the sequence of hGH resembles that of hPL much more closely than it does those of non-primate GHs, indicating that hPL arose following a duplication of the GH gene that occurred after the separation of the main orders of placental mammals. The hGH-V gene also resembles hGH-N very closely (the proteins are
about 93% of all
residues), probably recent origin by gene dupli¬ reflecting cation. However, the protein coded by the hGH-V gene is probably glycosylated (unlike hGH itself). Its biological properties differ from those of hGH (MacLeod et al. 1991) and its expression in the pla¬ centa but not the anterior pituitary gland suggests a distinct function during human gestation. There is at
an even more
no
evidence for
a
cluster of GH-like genes in the
non-primate mammals that have been studied, and it seems likely that the cluster seen in humans arose during the course of primate evolution by a series of gene duplications. lactogens and related proteins in non-primate mammals The occurrence of placental lactogens in various non-primate mammals has been suspected for many
Placental
characterization, with the clear demonstration that (unlike hPL) they resemble prolactins more than GHs, has only been achieved quite recently. It is now clear that in both ruminants and rodents there are complex sub-families of prolactinlike proteins that are produced in the placenta.
years, but detailed
Ruminants The situation in ruminants is particularly complex. Schuler et al. (1988) reported the amino acid sequence of bovine PL (bPL-Ala), but sequences of at least seven additional prolactin-like proteins from bovine placenta have now been determined, mainly via cDNA cloning (Kessler et al. 1989; Tanaka et al. 1989; Yamakawa et al. 1990; Tanaka et al. 1991). Their nomenclature has recently been revised, and all have been designated either placental lactogens
(PLs)
or
prolactin-related proteins (PRPs) (Schüler
al. 1991). Four were originally termed bovine pro¬ lactin-like proteins (bPLPs) I, II, III and IV (now respectively bPL-Val, bPRP-IV, bPRP-V and bPRP-VI), while the others were termed bovine pro¬ lactin-related cDNAs (bPRCs) I, II and III (now et
respectively bPRP-I, bPRP-II and bPRP-III). On
the basis of sequence similarities, these various pro¬ teins fall into five groups: (1) bPL-Ala and bPLVal (differing only by a single residue); (2) bPRP-I, bPRP-II and bPRP-IV; (3) bPRP-III; (4) bPRP-V; (5) bPRP-VI. The last is very unusual in lackjng the C-terminal disulphide loop that is present in all other members of the GH/prolactin protein family. Each group shows greater sequence similarity to bovine prolactin than to the sequence deduced for the pro¬ lactin of the 'ancestral placental mammal' (a sequence very similar to those of pig and whale prolactins; Wallis, 1981), suggesting that all of the prolactin-like hormones in the bovine placenta originated as a consequence of one or more duplica¬ tions of the prolactin gene that occurred after separa¬ tion of the main orders of placental mammals. Whether a single duplication of the prolactin gene gave rise to the placental hormones (with subsequent duplications of the 'PL/PRP' gene to give the various placental proteins), or whether several duplications of the prolactin gene itself occurred, is not yet clear. It is clear, however, that once the ruminant PL-like genes and proteins arose, their evolution was very rapid the differences between them are much greater than those between most of the mammalian prolactins. This rapid evolution is borne out by the characterization of ovine PL (Colosi et al. 1989), which is clearly homologous with its bovine coun¬ terpart, but differs from it at about 33% of all resi¬ dues (contrasting with 1% of all residues when ovine and bovine prolactins are compared). -
Rodents The prolactin-like proteins found in the rodent pla¬ centa also present a complex picture (reviewed by Southard & Talamantes, 1991). Two PLs (PL-I and PL-11) have been identified from rat, mouse and hamster (Duckworth et al. 1986; Jackson et al. 1986; Colosi et al. 1987; Southard et al. 1989; Robertson et al. 1990) and show considerable sequence similarity, although hamster PL-I I has the unusual feature of an additional disulphide bridge. At least four addi¬ tional prolactin-like proteins are expressed in rat pla¬ centa (rPLP-A, rPLP-B, rPLP-C and rPL-I variant) (Robertson et al. 1990; Deb et al. 1991; Robertson et al. 1991) and two quite different ones in mouse placenta (mPRP and proliferin) (Linzer & Nathans, 1984, 1985). Similarities between any two of these are no greater than similarity to prolactin (except that rPL-I and rPL-I variant show about 85% ident¬ ity). Analysis of the sequences of these various pro¬ teins indicates that although they are clearly prolactin-like, they resemble rat or mouse prolactin less closely than they do the sequence deduced for the 'ancestral placental mammal'. However, rodent
prolactins appear to have been evolving extremely rapidly (Wallis, 1981), and one cannot conclude from the data available whether the rodent PLs (and other rodent prolactin-like placental proteins) arose before or after separation of the main orders of pla¬
cental mammals. There thus appear to be at least three groups of PL-like hormones that have arisen independently in the GH/prolactin family (see Table 1 for summary). Their appearance is obviously associated with the appearance of the placenta during mammalian evolu¬ tion. Presumably, evolutionary development of placentation led to a need for new hormones for the control of fetal growth, fetal—maternal relations and mammary development, and to a new organ able to produce such hormones. Analysis of the sequences available suggests that these PL-like proteins evolved very rapidly once they appeared, contrasting with the slow underlying rate of evolution for GH and prolactin, and in accordance with previous sug¬ gestions that rates of evolution in this family have been very variable (Wallis, 1981). The biological role of these proteins is poorly understood, although observations that the different placental proteins are expressed at different times during the course of pregnancy (e.g. Robertson et al. 1990) suggest that they do have separate and clear-cut roles in the con¬ trol of fetal and/or maternal development. The phy¬ siology and biochemistry of these many new placental proteins will need intensive study if our understanding of their functions is to keep pace with the rate at which they are being discovered.
Somatolactin
prolactin themselves probably arose follow¬ gene duplication which occurred early in the
GH and
ing
a
evolution of vertebrates or chordates; the two have been established as separate hormones in most fish groups as well as in tetrapods. The recent charac¬ terization of a new pituitary protein, named somato¬ lactin, in teleost fish, including flounder (Ono et al. 1990), cod (Rand-Weaver et al. 1991) and salmon (Takayama et al. 1991ft), has provided a new member of the GH/prolactin family which is about equally similar to GH and prolactin, and which may have arisen at about the same time that these two hor¬ mones diverged. As in other groups, teleost GH and prolactin are found in the anterior lobe of the pitu¬ itary gland. Somatolactin was isolated from the inter¬ mediate lobe of this gland, which in teleosts contains two main secretory cell types, one of which produces a melanocyte-stimulating hormone (equivalent to that found in the intermediate lobe of many mam¬ mals) while the other (the PIPAS cell) is rich in glycoprotein and appears to be involved in responses
table
1. Proteins of the
GH/prolactin family Species
GH-like proteins** GH GH variant Human PL hCS-L
GH/prolactin-like proteins Somatolactin Prolactin-like proteins Prolactin Rodent placental proteins PL-I PL-II PL-I variant
Proliferin PRP PLP-A PLP-B
PLP-C Ruminant PL PRP-1 PRP-11
PRP-IV PRP-III PRP-V PRP-VI
placenta] proteins
distribution*
Tissue of
expression
Most vertebrates Human Human (primates?) Human
Anterior pituitary Placenta Placenta Placenta?
Teleost fish
Pituitary (intermediate lobe)
Most vertebrates
Anterior
Mouse, rat Mouse, rat, hamster
Placenta Placenta Placenta
Rat Mouse Mouse Rat Rat Rat
Placenta;
pituitary
some
proliferating
cells
Placenta Placenta Placenta Placenta
Ox, sheep
Placenta Placenta Placenta Placenta Placenta Placenta Placenta
Ox Ox Ox Ox Ox Ox
distribution indicates those groups for which a sequence has been reported. Omission of a species or group from the list does not necessarily indicate that the protein does not occur there. **Variants of GH and prolactin produced by post-transcriptional (e.g. 20 kDa human GH) or post-translational processing are not included. PL, placental lactogen; hCS, human choriomammosomatotrophin; PRP, prolactin-related protein; PLP, prolactinlike protein.
*Species
relating to environmental changes. The main glycoprotein in the PIPAS cell of the flounder is somato¬ lactin, which has now been isolated and characterized, and for which the cDNA has been cloned (Ono et al. 1990). The sequence of this cDNA
indicates that the precursor of somatolactin contains 231 amino acid residues, including a signal sequence of 24 residues. The mature somatolactin thus con¬ tains 207 residues, including a single potential glyco¬ sylation site and seven half-cystine residues. Somatolactin shows sequence similarity with both GHs (24-28% identity) and prolactins (23-26% identity), and a similar degree of similarity to placen¬ tal lactogens and proliferin. Ono et al. (1990) have concluded that it arose as the consequence of a gene duplication that occurred after the separation of GH and prolactin but before the separation of the lines giving rise to teleosts and tetrapods. There is a good deal of evidence that somatolactin plays a role in adaptation of fish to environmental variations, including (depending on the species) dark back¬ ground, acidic pH, low Ca concentration and low osmolarity. It is possible that the hormone may occur quite widely in the vertebrates (Ono et al. 1990), but the evidence for its occurrence in mammals is rather tenuous. In fish, somatolactin
strongly conserved than corresponding GHs (Takayama et al.
sequences appear to be more
those of the
1991a). The
cytokine family
In the past few years, receptors for GH and prolactin have been characterized by cDNA cloning and sequ¬ encing (reviewed by Kelly et al. 1991). They have been shown to have several features in common with the receptors for a number of cytokines (such as erythropoietin, interleukins-2, -3, -4, -5, -6 and -7 and colony-stimulating factors), including some sequence similarity. This strongly suggests that these proteins are related phylogenetically and rep¬ resent a superfamily. The question then arises as to whether the ligands for these receptors may also be related. The tertiary structures of several of these hormones and cytokines have now been determined or predicted, and at this level there are resemblances (though such resemblances are difficult to detect at the level of amino acid sequence, possibly because of divergent evolution). The tertiary structure of GH (Abdel-Meguid et al. 1987) shows a char¬ acteristic four-helical bundle with an unusual and
characteristic arrangement of the a-helices ('up-updown-down'). Four-helical bundles with the same arrangement of a-helices have been reported for interleukin-4 (Redfield et al. 1991) and predicted for erythropoietin, interleukin-6 and granulocyte colony-stimulating factor (reviewed by Bazan, 1990). It seems unlikely that this is a coincidence, and it is at least possible that GH, prolactin and the placental lactogens are members of a larger superfamily of hormones and cytokines which share struc¬ tural features, have similar mechanisms of action (in view of similarities between their receptors) and may have had a common evolutionary origin. This idea may have major implications for the way that we view these important regulatory proteins; the GH/ prolactin family is not only expanding, but is dis¬ covering distant relations which were previously
unsuspected.
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Biochemistry Laboratory, School of Biological Sciences, University of Sussex, Brighton BN1 9QG, U.K.
