Autocrine Regulation of Keratinocytes: The Emerging Role of Heparin-Binding, Epidermal Growth Factor-Related Growth Factors
1998; Elsevier BV; Volume: 111; Issue: 5 Linguagem: Inglês
10.1046/j.1523-1747.1998.00390.x
ISSN1523-1747
AutoresMichael W. Piepkorn, Mark R. Pittelkow, Paul W. Cook,
Tópico(s)HER2/EGFR in Cancer Research
ResumoAlthough originally conceived as a basis for malignant cell growth, autocrine signaling networks are currently known to be activated during tissue repair and with in vitro cultivation. In human epidermal keratinocytes, activation of the epidermal growth factor receptor by cognate ligands mediates the majority of the autonomous replicative capacity of these cells and is necessary to inhibit differentiation and apoptosis. The importance of heparin-binding growth factors in activation of this receptor was first suggested by the strong anti-proliferative effects of soluble heparin-like molecules on keratinocyte growth. This and related evidence led to the identification of amphiregulin as a major autocrine factor for keratinocytes. The binding of amphiregulin and its homolog, heparin-binding epidermal growth factor-like growth factor, to the receptor is potentially amplified by autoinduction and cross-signaling through epidermal growth factor-related polypeptides and by transmodulation of other ErbB-family receptors (HER-2, -3, -4) in cells expressing these receptors. Heparan sulfate proteoglycans and the tetraspanin family of membrane-associated proteins appear to act as cofactors in amphiregulin-driven mitogenesis mediated by the epidermal growth factor receptor, but amphiregulin's immunolocalization to keratinocyte nuclei and to filopodia may indicate other potentially novel effects. Following from the observation that amphiregulin is overexpressed in lesional psoriatic epidermis, the importance of amphiregulin in hyperproliferative skin diseases has been further supported by recent studies of the targeted expression of a transgene encoding keratin 14 promoter-driven human amphiregulin to the basal epidermis of mice. Founder transgenic mice displayed a morphologic and microscopic cutaneous phenotype that shares characteristics with psoriasis. Pharmacologic regulation of amphiregulin's expression and receptor signaling may eventually prove to be an effective strategy in the treatment of hyperproliferative skin diseases. Although originally conceived as a basis for malignant cell growth, autocrine signaling networks are currently known to be activated during tissue repair and with in vitro cultivation. In human epidermal keratinocytes, activation of the epidermal growth factor receptor by cognate ligands mediates the majority of the autonomous replicative capacity of these cells and is necessary to inhibit differentiation and apoptosis. The importance of heparin-binding growth factors in activation of this receptor was first suggested by the strong anti-proliferative effects of soluble heparin-like molecules on keratinocyte growth. This and related evidence led to the identification of amphiregulin as a major autocrine factor for keratinocytes. The binding of amphiregulin and its homolog, heparin-binding epidermal growth factor-like growth factor, to the receptor is potentially amplified by autoinduction and cross-signaling through epidermal growth factor-related polypeptides and by transmodulation of other ErbB-family receptors (HER-2, -3, -4) in cells expressing these receptors. Heparan sulfate proteoglycans and the tetraspanin family of membrane-associated proteins appear to act as cofactors in amphiregulin-driven mitogenesis mediated by the epidermal growth factor receptor, but amphiregulin's immunolocalization to keratinocyte nuclei and to filopodia may indicate other potentially novel effects. Following from the observation that amphiregulin is overexpressed in lesional psoriatic epidermis, the importance of amphiregulin in hyperproliferative skin diseases has been further supported by recent studies of the targeted expression of a transgene encoding keratin 14 promoter-driven human amphiregulin to the basal epidermis of mice. Founder transgenic mice displayed a morphologic and microscopic cutaneous phenotype that shares characteristics with psoriasis. Pharmacologic regulation of amphiregulin's expression and receptor signaling may eventually prove to be an effective strategy in the treatment of hyperproliferative skin diseases. amphiregulin epidermal growth factor receptor heparinbinding epidermal growth factor The concept of autocrine cellular signaling was originally invoked to explain the unregulated, autonomous proliferation of malignant cells (Sporn and Todaro, 1980Sporn M.B. Todaro G.J. Autocrine secretion and malignant transformation of cells.N Engl J Med. 1980; 303: 878-880Crossref PubMed Scopus (1085) Google Scholar). It was postulated that dysregulated cellular proliferation results from endogenous production of growth-promoting polypeptides (transforming growth factors) and constitutive activation of cognate receptors, thereby supplanting the dependency on exogenous growth factors. The model further postulated that these mechanisms do not normally function in nontransformed cells except during embryogenesis, but that inappropriate and coordinate expression of these factors is activated with malignant transformation (Sporn and Todaro, 1980Sporn M.B. Todaro G.J. Autocrine secretion and malignant transformation of cells.N Engl J Med. 1980; 303: 878-880Crossref PubMed Scopus (1085) Google Scholar;Alexander and Currie, 1984Alexander P. Currie G. Concomitant synthesis of growth factors and their receptors – an aspect of malignant transformation.Biochem Pharmacol. 1984; 33: 941-943Crossref PubMed Scopus (3) Google Scholar). Notably, much of the investigations supporting these original tenets derived from in vitro studies on rodent fibroblasts. Revisions of the concept followed the discovery that autocrine pathways are expressed in normal cells and are inducible under various situations, such as during tissue repair (Stiles, 1984Stiles C.D. Autocrine control of growth?.Nature. 1984; 311: 604-605Crossref PubMed Scopus (14) Google Scholar;Marikovsky et al., 1993Marikovsky M. Breuing K. Liu P.Y. et al.Appearance ofheparin-binding EGF-like growth factor in would fluid as a response to injury.Proc Natl Acad Sci USA. 1993; 90: 3889-3893Crossref PubMed Scopus (290) Google Scholar;Liou et al., 1997Liou A. Elias P.M. Grunfeld C. Feingold K.R. Wood L.C. Amphiregulin and nerve growth factor expression are regulated by barrier status in murine epidermis.J Invest Derm. 1997; 108: 73-77Abstract Full Text PDF PubMed Scopus (48) Google Scholar) or when normal epithelial cells such as epidermal keratinocytes and mammary epithelial cells are cultured in vitro (Coffey et al., 1987aCoffey Jr, W. Derynck R. Wilcox J.N. Bringman T.S. Goustin A.S. Moses B.L. Pittelkow M.R. Production and autoinduction of transforming growth factor-α in human keratinocytes.Nature. 1987; 328: 817-820Crossref PubMed Scopus (674) Google Scholar,b;Shipley et al., 1989Shipley G.D. Keeble W.W. Hendrickson J.E. Coffey R.J. Pittelkow M.R. Growth of normal human keratinocytes and fibroblasts in serum-free medium is stimulated by acidic and basic fibroblast growth factor.J Cell Physiol. 1989; 138: 511-518Crossref PubMed Scopus (136) Google Scholar;Cook et al., 1991aCook P.W. Pittelkow M.R. Shipley G.D. Growth factor-independent proliferation of normal human neonatal keratinocytes: production of autocrine- and paracrine-acting mitogenic factors.J Cell Physiol. 1991; 146: 277-289Crossref PubMed Scopus (87) Google Scholar;Li and Shipley, 1991Li S. Shipley G.D. Expression of multiple species of basic fibroblast growth factor niRNA and protein in normal and tumor-derived mammary epithelial cells in culture.Cell Growth Diff. 1991; 2: 195-202PubMed Google Scholar;Li et al., 1992Li S. Plowman G.D. Buckley S.D. Shipley G.D. Heparin inhibition of autonomous growth implicates amphiregulin as an autocrine growth factor for normal human mammary epithelial cells.J Cell Physiol. 1992; 153: 103-111Crossref PubMed Scopus (69) Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar;Stoll et al., 1997Stoll S. Ciarner W. Elder J. Heparin-binding ligands mediate autocrine epidermal growth factor receptor activation in skin organ culture.J Clin Invest. 1997; 100: 1271-1281Crossref PubMed Scopus (99) Google Scholar). Following from our current understanding of autocrine regulation of various epithelial tissues and organs, autocrine dysregulation emerges as a potential mechanism contributing to the pathophysiology of those disease states that manifest aberrant hyperproliferation. Thus, the growth factors of autocrine regulatory networks hold promise as targets for therapeutic intervention through pharmacologic control of their expression, interaction with cognate cell surface receptors, or their coupled downstream signal transduction pathways. Contrary to early claims that only malignantly transformed cells display autocrine-driven proliferation in culture (Sporn and Todaro, 1980Sporn M.B. Todaro G.J. Autocrine secretion and malignant transformation of cells.N Engl J Med. 1980; 303: 878-880Crossref PubMed Scopus (1085) Google Scholar;Alexander and Currie, 1984Alexander P. Currie G. Concomitant synthesis of growth factors and their receptors – an aspect of malignant transformation.Biochem Pharmacol. 1984; 33: 941-943Crossref PubMed Scopus (3) Google Scholar), we and others have shown that normal human keratinocytes exhibit autonomous (autocrine growth factor driven) proliferation when cultured at cell densities above 1 × 103 cells per cm2 (Shipley et al., 1989Shipley G.D. Keeble W.W. Hendrickson J.E. Coffey R.J. Pittelkow M.R. Growth of normal human keratinocytes and fibroblasts in serum-free medium is stimulated by acidic and basic fibroblast growth factor.J Cell Physiol. 1989; 138: 511-518Crossref PubMed Scopus (136) Google Scholar;Cook et al., 1991aCook P.W. Pittelkow M.R. Shipley G.D. Growth factor-independent proliferation of normal human neonatal keratinocytes: production of autocrine- and paracrine-acting mitogenic factors.J Cell Physiol. 1991; 146: 277-289Crossref PubMed Scopus (87) Google Scholar;Pittelkow et al., 1993Pittelkow M.R. Cook P.W. Shipley G.D. Derynck R. Coffey Jr, W. Autonomous growth of human keratinocytes requires epidermal growth factor receptor occupancy.Cell Growth Differentiation. 1993; 4: 513-521PubMed Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar). With the exception of acidic fibroblast growth factor and keratinocyte growth factor, human keratinocytes appear to require binding of epidermal growth factor (EGF) or other family member ligands to the EGF receptor (EGFR, human EGFR-1, or HER-1) to sustain proliferation in culture (Rheinwald and Green, 1977Rheinwald J. Green H. Epidermal growth factor and the multiplication of human epidermal keratinocytes.Nature. 1977; 265: 421-424Crossref PubMed Scopus (809) Google Scholar;Finch et al., 1989Finch P.W. Rubin J.S. Mike T. Ron D. Aaronson S.A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth.Science. 1989; 245: 752-755Crossref PubMed Scopus (794) Google Scholar;Shipley et al., 1989Shipley G.D. Keeble W.W. Hendrickson J.E. Coffey R.J. Pittelkow M.R. Growth of normal human keratinocytes and fibroblasts in serum-free medium is stimulated by acidic and basic fibroblast growth factor.J Cell Physiol. 1989; 138: 511-518Crossref PubMed Scopus (136) Google Scholar;Pittelkow et al., 1993Pittelkow M.R. Cook P.W. Shipley G.D. Derynck R. Coffey Jr, W. Autonomous growth of human keratinocytes requires epidermal growth factor receptor occupancy.Cell Growth Differentiation. 1993; 4: 513-521PubMed Google Scholar). Current understanding of autocrine signaling in epidermal keratinocytes thus assigns a principal function to the EGFR/HER-1 and its specific ligands. The primary role of the EGF receptor-ligand system as an endogenous signaling axis in keratinocytes is reflected by the observation that blocking antibody against the EGFR inhibits greater than –90% of autocrine growth of these cells in vitro (Cook et al., 1991bCook P.W. Mattox P.A. Keeble W.W. et al.A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.Mol Cell Biol. 1991; 11: 2547-2557Crossref PubMed Scopus (200) Google Scholar;Pittelkow et al., 1993Pittelkow M.R. Cook P.W. Shipley G.D. Derynck R. Coffey Jr, W. Autonomous growth of human keratinocytes requires epidermal growth factor receptor occupancy.Cell Growth Differentiation. 1993; 4: 513-521PubMed Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar;Ristow, 1996Ristow H.-J. Studies on stimulation of DNA synthesis with epidermal growth factor and insulinlike growth factor-1 in cultured human keratinocytes.Growth Regulation. 1996; 6: 96-109PubMed Google Scholar;Peus et al., 1997Peus D. Hamacher L. Pittelkow M. EGF-receptor tyrosine kinase inhibition induces keratinocyte growth arrest and terminal differentiation.J Invest Derm. 1997; 109: 751-756Abstract Full Text PDF PubMed Scopus (142) Google Scholar). More recent investigation has also demonstrated that interruption of the activity of EGF-related autocrine growth factors in human keratinocytes by neutralizing antibody to the EGFR, or a specific inhibitor of the EGFR tyrosine kinase (PD 153035), not only causes cessation of keratinocyte proliferation, but also induces irreversible growth arrest and terminal differentiation (Peus et al., 1997Peus D. Hamacher L. Pittelkow M. EGF-receptor tyrosine kinase inhibition induces keratinocyte growth arrest and terminal differentiation.J Invest Derm. 1997; 109: 751-756Abstract Full Text PDF PubMed Scopus (142) Google Scholar). The correlation between keratinocyte proliferation and expression of the EGFR is further illustrated by immunolabeling, which localizes the receptor to the proliferative basal compartment in adult epidermis, as well as to all epidermal layers and appendages of fetal skin (Nanney et al., 1990Nanney L.B. Stoscheck C.M. King Jr, Le Underwood R.A. Holbrook K.A. Immunolocalization of epidermal growth factor receptors in normal developing human skin.J Invest Dermatol. 1990; 94: 742-748Abstract Full Text PDF PubMed Google Scholar;Sakai et al., 1994Sakai Y. Nelson K.G. Snedeker S. Bossert N.L. Walker W. McLachlan J. Di Augustine R.P. Expression of epidermal growth factor in suprabasal cells of stratified squamous epithelia: implications for a role in differentiation.Cell Growth Diff. 1994; 5: 527-535PubMed Google Scholar). EGFR null mice, moreover, exhibit severe epidermal atrophy, markedly diminished basal rates of epidermal keratinocyte replication, and premature differentiation (Miettinen et al., 1995Miettinen P.J. Berger J.E. Meneses J. Phung Y. Pedersen R.A. Werb Z. Derynck R. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor.Nature. 1995; 376: 337-341Crossref PubMed Scopus (842) Google Scholar;Sibilia and Wagner, 1995Sibilia M. Wagner E. Strain-dependent epithelial defects in mice lacking the EGF receptor.Science. 1995; 269: 234-238Crossref PubMed Scopus (828) Google Scholar;Threadgill et al., 1995Threadgill D.W. Dlugosz A.A. Hansen L.A. et al.Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.Science. 1995; 269: 230-234Crossref PubMed Scopus (1216) Google Scholar). EGF and its homolog, transforming growth factor-α (TGF-α), were originally considered the principal ligands for the EGFR in keratinocytes (Rheinwald and Green, 1977Rheinwald J. Green H. Epidermal growth factor and the multiplication of human epidermal keratinocytes.Nature. 1977; 265: 421-424Crossref PubMed Scopus (809) Google Scholar;Wille et al., 1984Wille Jr, M. Pittelkow M.P. Shipley G.D. Scott R.E. Integrated control of growth and differentiation of normal human prokeratinocytes cultured in scrum-free medium: clonal analysis, growth kinetics, and cell cycle studies.J Cell Physiol. 1984; 121: 31-44Crossref PubMed Scopus (339) Google Scholar;Coffey et al., 1987aCoffey Jr, W. Derynck R. Wilcox J.N. Bringman T.S. Goustin A.S. Moses B.L. Pittelkow M.R. Production and autoinduction of transforming growth factor-α in human keratinocytes.Nature. 1987; 328: 817-820Crossref PubMed Scopus (674) Google Scholar,Coffey et al., 1987bCoffey R.J. Goustin A.S. Soderquist A.M. Shipley G.D. Wolfshol J. Carpenter G. Moses H.L. Transforming growth factor α and β expression in human colon cancer lines: Implications for an autocrine model.Cancer Res. 1987; 47: 4590-4594PubMed Google Scholar;Pittelkow et al., 1988Pittelkow M.R. Coffey R.J. Moses B.L. Keratinocytes 1 produce and are regulated by transforming growth factors.in: Milstone L.M. Edelson R.L. Endocrine, Metabolic and Immunologic Functions of Keratinocytes. Vol. 548. Ann NY Academy of Science, New York1988: 211-224Google Scholar,Pittelkow et al., 1989Pittelkow M.R. Lindquist P.B. Abraharn R.T. Graves-deal R. Derynck R. Coffey R.J. Induction of transforming growth factor-α expression in human keratinocytes by phorbol esters.J Biol Chem. 1989; 264: 5164-5171Abstract Full Text PDF PubMed Google Scholar). The importance of heparin-binding autocrine factors in keratinocytes, however, first emerged from the observation that exogenous heparin-like glycosaminoglycans strongly inhibit the autonomous growth of these cells (Shipley et al., 1989Shipley G.D. Keeble W.W. Hendrickson J.E. Coffey R.J. Pittelkow M.R. Growth of normal human keratinocytes and fibroblasts in serum-free medium is stimulated by acidic and basic fibroblast growth factor.J Cell Physiol. 1989; 138: 511-518Crossref PubMed Scopus (136) Google Scholar;Cook et al., 1991aCook P.W. Pittelkow M.R. Shipley G.D. Growth factor-independent proliferation of normal human neonatal keratinocytes: production of autocrine- and paracrine-acting mitogenic factors.J Cell Physiol. 1991; 146: 277-289Crossref PubMed Scopus (87) Google Scholar,Cook et al., 1992bCook P.W. Mattox P.A. Keeble W.W. Shipley G.D. Inhibition of autonomous human keratinocyte proliferation and amphiregulin mitogenic activity by sulfated polysaccharides.In Vitro Cell Dev Biol. 1992; 28A: 218-222Crossref PubMed Scopus (25) Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar), whereas both EGF and TGF-α were shown to lack heparin-binding and heparin-mediated regulation in human keratinocytes (Cook et al., 1991bCook P.W. Mattox P.A. Keeble W.W. et al.A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.Mol Cell Biol. 1991; 11: 2547-2557Crossref PubMed Scopus (200) Google Scholar). Juxtacrine-mediated autonomous growth has also been implicated in normal keratinocytes as we have shown that colonies of at least 4–10 cells are required for the heparin-inhibitable, EGF-receptor-dependent clonal expansion of these cells in the absence of exogenous growth factors (Pittelkow et al., 1993Pittelkow M.R. Cook P.W. Shipley G.D. Derynck R. Coffey Jr, W. Autonomous growth of human keratinocytes requires epidermal growth factor receptor occupancy.Cell Growth Differentiation. 1993; 4: 513-521PubMed Google Scholar). Subsequently, as the list of EGF homologs has expanded, several ligands have been identified with binding affinity for heparinoids. Specifically, an EGF-related ligand named amphiregulin (AR) has been implicated in mediating the autocrine growth and heparin-dependent growth inhibition of normal epithelial (e.g., epidermal or mammary) cells derived from ectoderm (Cook et al., 1991aCook P.W. Pittelkow M.R. Shipley G.D. Growth factor-independent proliferation of normal human neonatal keratinocytes: production of autocrine- and paracrine-acting mitogenic factors.J Cell Physiol. 1991; 146: 277-289Crossref PubMed Scopus (87) Google Scholar;Li and Shipley, 1991Li S. Shipley G.D. Expression of multiple species of basic fibroblast growth factor niRNA and protein in normal and tumor-derived mammary epithelial cells in culture.Cell Growth Diff. 1991; 2: 195-202PubMed Google Scholar, 1992b;Li et al., 1992Li S. Plowman G.D. Buckley S.D. Shipley G.D. Heparin inhibition of autonomous growth implicates amphiregulin as an autocrine growth factor for normal human mammary epithelial cells.J Cell Physiol. 1992; 153: 103-111Crossref PubMed Scopus (69) Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar). AR is a member of the EGF family with sequence homology within its carboxy-terminal domain to EGF and TGF-α (Shoyab et al., 1988Shoyab M. McDonald V.L. Bradley J.G. Todaro G.J. Amphiregulin: a biflanctional growthmodulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7.Proc Natl Acad Sci USA. 1988; 85: 6528-6532Crossref PubMed Scopus (277) Google Scholar,Shoyab et al., 1989Shoyab M. Plowman G.D. McDonald V.L. Bradley J.G. Todaro G.J. Structure and function of human amphiregulin: a member of the epidermal growth factor family.Science. 1989; 243: 1074-1076Crossref PubMed Scopus (473) Google Scholar;Plowman et al., 1990Plowman G.D. Green J.M. McDonald V.L. Neubauer M.G. Disteche C.M. Todaro G.J. Shoyab M. The amphiregulin gene encodes a novel epidermal growth factor-related protein with turnorinhibitory activity.Mol Cell Biol. 1990; 10: 1969-1981Crossref PubMed Scopus (313) Google Scholar;Cook et al., 1991bCook P.W. Mattox P.A. Keeble W.W. et al.A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.Mol Cell Biol. 1991; 11: 2547-2557Crossref PubMed Scopus (200) Google Scholar) and is presently identified as a major autocrine factor responsible for the autonomous proliferation of human keratinocytes when cultured under serum free conditions in the absence of exogenous EGF or bovine pituitary extract (Cook et al., 1991bCook P.W. Mattox P.A. Keeble W.W. et al.A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.Mol Cell Biol. 1991; 11: 2547-2557Crossref PubMed Scopus (200) Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar). The homolog, heparin-binding EGF-like growth factor (HB-EGF) (Higashiyama et al., 1992Higashiyama S. Lau K. Besner G.E. Abraham J.A. Klagsbrun M. Structure of heparin-binding EGF-like growth flactor.J Biol Chem. 1992; 267: 6205-6212Abstract Full Text PDF PubMed Google Scholar), may also exert some autocrine effects in these cells (Hashimoto et al., 1994Hashimoto Y. Higashiyama S. Asada H. et al.Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes.J Biol Chem. 1994; 269: 20060-20066Abstract Full Text PDF PubMed Google Scholar). By blocking antibody studies, AR and HB-EGF account for –70% (Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar) and less than 30% (Hashimoto et al., 1994Hashimoto Y. Higashiyama S. Asada H. et al.Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes.J Biol Chem. 1994; 269: 20060-20066Abstract Full Text PDF PubMed Google Scholar), respectively, of autocrine-dependent proliferation. The molar mitogenic potency of human recombinant AR with murine and human keratinocytes is also comparable with that of EGF (Shoyab et al., 1989Shoyab M. Plowman G.D. McDonald V.L. Bradley J.G. Todaro G.J. Structure and function of human amphiregulin: a member of the epidermal growth factor family.Science. 1989; 243: 1074-1076Crossref PubMed Scopus (473) Google Scholar;Cook et al., 1991bCook P.W. Mattox P.A. Keeble W.W. et al.A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.Mol Cell Biol. 1991; 11: 2547-2557Crossref PubMed Scopus (200) Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar). Because HB-EGF shares with AR a strong sequence homology (Higashiyama et al., 1992Higashiyama S. Lau K. Besner G.E. Abraham J.A. Klagsbrun M. Structure of heparin-binding EGF-like growth flactor.J Biol Chem. 1992; 267: 6205-6212Abstract Full Text PDF PubMed Google Scholar), a common pathway of signal transduction through the EGFR (Higashiyama et al., 1992Higashiyama S. Lau K. Besner G.E. Abraham J.A. Klagsbrun M. Structure of heparin-binding EGF-like growth flactor.J Biol Chem. 1992; 267: 6205-6212Abstract Full Text PDF PubMed Google Scholar), and an apparent requirement for cell surface heparin-like glycosaminoglycans as cofactors in at least some cell lineages (Higashiyama et al., 1993Higashiyama S. Abraham J.A. Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate.J Cell Biol. 1993; 122: 933-940Crossref PubMed Scopus (308) Google Scholar;Aviezer and Yayon, 1994Aviezer D. Yayon A. Heparin-dependent binding and autophosphorylation of epidermal growth factor (EGF) receptor by heparin-binding EGF-like growth factor but not by EG17.Proc Natl Acad Sci USA. 1994; 91: 12173-12177Crossref PubMed Scopus (122) Google Scholar;Johnson and Wong, 1994Johnson G.R. Wong L. Heparan sulfate is essential to amphiregulin-induced mitogenic signaling by the epidermal growth factor receptor.J Biol Chem. 1994; 269: 27149-27154Abstract Full Text PDF PubMed Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human keratinocytes: autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin-like glycosarninoglycans.J Cell Physiol. 1994; 159: 114-120Crossref PubMed Scopus (91) Google Scholar;Thompson et al., 1994Thompson S.A. Higashiyama S. Wood K. et al.Characterization of sequences within heparin-binding EGF-like growth factor that mediate interaction with heparin.J Biol Chem. 1994; 269: 2541-2549Abstract Full Text PDF PubMed Google Scholar;Cook et al., 1995bCook P.W. Ashton N.W. Karkaria C.E. Siess D.C. Shipley G.D. Differential effects of a heparin antagonist (hexadimethrine) or chlorate on amphiregulin, basic fibroblast growth factor, and heparin-binding EGF-like growth factor activity.J Cell Physiol. 1995; 163: 418-429Crossref PubMed Scopus (27) Google Scholar), it is presumed for the purposes of this overview that the functional activities of the two factors are similar and, perhaps, partly redundant. One curious difference, however, is that the mitogenic activity of HB-EGF in various cells including keratinocytes is variably potentiated by soluble heparinoids (Marikovsky et al., 1993Marikovsky M. Breuing K. Liu P.Y. et al.Appearance ofheparin-binding EGF-like growth factor in would fluid as a response to injury.Proc Natl Acad Sci USA. 1993; 90: 3889-3893Crossref PubMed Scopus (290) Google Scholar;Cook et al., 1995aCook P.W. Damm D. Garrick B.L. et al.Carboxyl-terminal truncation of Leucine76 converts heparin-binding EGF-like growth factor from a heparin-enhancible to a heparin-suppressible growth factor.J Cell Phyiol. 1995; 163: 407-417Crossref PubMed Scopus (16) Google Scholar), in stark contrast to their attenuative effects on AR signaling (Cook et al., 1991bCook P.W. Mattox P.A. Keeble W.W. et al.A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.Mol Cell Biol. 1991; 11: 2547-2557Crossref PubMed Scopus (200) Google Scholar,Cook et al., 1992bCook P.W. Mattox P.A. Keeble W.W. Shipley G.D. Inhibition of autonomous human keratinocyte proliferation and amphiregulin mitogenic activity by sulfated polysaccharides.In Vitro Cell Dev Biol. 1992; 28A: 218-222Crossref PubMed Scopus (25) Google Scholar,Cook et al., 1995aCook P.W. Damm D. Garrick B.L. et al.Carboxyl-terminal truncation of Leucine76 converts heparin-binding EGF-like growth factor from a heparin-enhancible to a heparin-suppressible growth factor.J Cell Phyiol. 1995; 163: 407-417Crossref PubMed Scopus (16) Google Scholar;Piepkorn et al., 1994Piepkorn M. Lo Q. Plowman G. Amphiregulin-dependent proliferation of cultured human kera
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