Metalloproteinase-mediated, Context-dependent Function of Amphiregulin and HB-EGF in Human Keratinocytes and Skin

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2009 Jul 18

PMID 19609315

Citations 24

Authors

Stefan W Stoll

Jessica L Johnson

Ajay Bhasin

Andrew Johnston

Johann E Gudjonsson

Laure Rittie

James T Elder

Affiliations

Soon will be listed here.

Abstract

Human keratinocytes (KCs) express multiple EGF receptor (EGFR) ligands; however, their functions in specific cellular contexts remain largely undefined. To address this issue, first we measured mRNA and protein levels for multiple EGFR ligands in KCs and skin. Amphiregulin (AREG) was by far the most abundant EGFR ligand in cultured KCs, with >19 times more mRNA and >7.5 times more shed protein than any other family member. EGFR ligand expression in normal skin was low (<8 per thousand of RPLP0/36B4); however, HB-EGF and AREG mRNAs were strongly induced in human skin organ culture. KC migration in scratch wound assays was highly metalloproteinase (MP)- and EGFR dependent, and was markedly inhibited by EGFR ligand antibodies. However, lentivirus-mediated expression of soluble HB-EGF, but not soluble AREG, strongly enhanced KC migration, even in the presence of MP inhibitors. Lysophosphatidic acid (LPA)-induced ERK phosphorylation was also strongly EGFR and MP dependent and markedly inhibited by neutralization of HB-EGF. In contrast, autocrine KC proliferation and ERK phosphorylation were selectively blocked by neutralization of AREG. These data show that distinct EGFR ligands stimulate KC behavior in different cellular contexts, and in an MP-dependent fashion.

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References

Press M, Cordon-Cardo C, Slamon D . Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990; 5(7):953-62. View

Singh A, Tsukada T, Zent R, Harris R . Membrane-associated HB-EGF modulates HGF-induced cellular responses in MDCK cells. J Cell Sci. 2004; 117(Pt 8):1365-79. DOI: 10.1242/jcs.01037. View

Rittie L, Kansra S, Stoll S, Li Y, Gudjonsson J, Shao Y . Differential ErbB1 signaling in squamous cell versus basal cell carcinoma of the skin. Am J Pathol. 2007; 170(6):2089-99. PMC: 1899432. DOI: 10.2353/ajpath.2007.060537. View

Danilenko D, Ring B, Lu J, Tarpley J, Chang D, Liu N . Neu differentiation factor upregulates epidermal migration and integrin expression in excisional wounds. J Clin Invest. 1995; 95(2):842-51. PMC: 295566. DOI: 10.1172/JCI117734. View

Jackson L, Qiu T, Sunnarborg S, Chang A, Zhang C, Patterson C . Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J. 2003; 22(11):2704-16. PMC: 156761. DOI: 10.1093/emboj/cdg264. View

Kranenburg O, Moolenaar W . Ras-MAP kinase signaling by lysophosphatidic acid and other G protein-coupled receptor agonists. Oncogene. 2001; 20(13):1540-6. DOI: 10.1038/sj.onc.1204187. View

Cook P, Brown J, Cornell K, Pittelkow M . Suprabasal expression of human amphiregulin in the epidermis of transgenic mice induces a severe, early-onset, psoriasis-like skin pathology: expression of amphiregulin in the basal epidermis is also associated with synovitis. Exp Dermatol. 2004; 13(6):347-56. DOI: 10.1111/j.0906-6705.2004.00183.x. View

Cook P, Piepkorn M, Clegg C, Plowman G, DeMay J, Brown J . Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J Clin Invest. 1997; 100(9):2286-94. PMC: 508424. DOI: 10.1172/JCI119766. View

Shirakata Y, Kimura R, Nanba D, Iwamoto R, Tokumaru S, Morimoto C . Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing. J Cell Sci. 2005; 118(Pt 11):2363-70. DOI: 10.1242/jcs.02346. View

10.

Klein S, Fisher G, Jensen T, Mendelsohn J, Voorhees J, Elder J . Regulation of TGF-alpha expression in human keratinocytes: PKC-dependent and -independent pathways. J Cell Physiol. 1992; 151(2):326-36. DOI: 10.1002/jcp.1041510214. View

11.

Sanderson M, Dempsey P, Dunbar A . Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors. Growth Factors. 2006; 24(2):121-36. DOI: 10.1080/08977190600634373. View

12.

Dickson M, Hahn W, Ino Y, Ronfard V, Wu J, Weinberg R . Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol Cell Biol. 2000; 20(4):1436-47. PMC: 85304. DOI: 10.1128/MCB.20.4.1436-1447.2000. View

13.

Kochupurakkal B, Harari D, Di-Segni A, Maik-Rachline G, Lyass L, Gur G . Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J Biol Chem. 2004; 280(9):8503-12. DOI: 10.1074/jbc.M413919200. View

14.

Schelfhout V, Coene E, Delaey B, Waeytens A, De Rycke L, Deleu M . The role of heregulin-alpha as a motility factor and amphiregulin as a growth factor in wound healing. J Pathol. 2002; 198(4):523-33. DOI: 10.1002/path.1240. View

15.

Hashimoto K, Higashiyama S, Asada H, Hashimura E, Kobayashi T, Sudo K . Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes. J Biol Chem. 1994; 269(31):20060-6. View

16.

Stoll S, Kansra S, Elder J . Keratinocyte outgrowth from human skin explant cultures is dependent upon p38 signaling. Wound Repair Regen. 2003; 11(5):346-53. DOI: 10.1046/j.1524-475x.2003.11506.x. View

17.

De Potter I, Poumay Y, Squillace K, Pittelkow M . Human EGF receptor (HER) family and heregulin members are differentially expressed in epidermal keratinocytes and modulate differentiation. Exp Cell Res. 2001; 271(2):315-28. DOI: 10.1006/excr.2001.5390. View

18.

Minner F, Poumay Y . Candidate housekeeping genes require evaluation before their selection for studies of human epidermal keratinocytes. J Invest Dermatol. 2008; 129(3):770-3. DOI: 10.1038/jid.2008.247. View

19.

Pittelkow M, Cook P, Shipley G, Derynck R, Coffey Jr R . Autonomous growth of human keratinocytes requires epidermal growth factor receptor occupancy. Cell Growth Differ. 1993; 4(6):513-21. View

20.

Watterson K, Lanning D, Diegelmann R, Spiegel S . Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing. Wound Repair Regen. 2007; 15(5):607-16. DOI: 10.1111/j.1524-475X.2007.00292.x. View