title: The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling.
abstract: Mice deficient for cathepsin L (CTSL) show epidermal hyperplasia due to a hyperproliferation of basal keratinocytes. Here we show that the critical function of CTSL in the skin is keratinocyte specific. This is revealed by transgenic re-expression of CTSL in the keratinocytes of ctsl-/- mice, resulting in a rescue of the ctsl-/- skin phenotype. Cultivation of primary mouse keratinocytes with fibroblast- and keratinocyte-conditioned media, as well as heterologous organotypic co-cultures of mouse fibroblasts and human keratinocytes, showed that the altered keratinocyte proliferation is caused primarily by CTSL-deficiency in keratinocytes. In the absence of EGF, wild type and CTSL-knockout keratinocytes proliferate with the same rates, while in presence of EGF, ctsl-/- keratinocytes showed enhanced proliferation compared with controls. Internalization and degradation of radioactively labeled EGF was identical in both ctsl-/- and ctsl+/+ keratinocytes. However, ctsl-/- keratinocytes recycled more EGF to the cell surface, where it is bound to the EGF-receptor, which is also more abundant in ctsl-/- cells. We conclude that the hyperproliferation of keratinocytes in CTSL-knockout mice is caused by an enhanced recycling of growth factors and growth factor receptors from the endosomes to the keratinocyte plasma membrane, which result in sustained growth stimulation.
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, 79106 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Sascha
authors.initials: S
authors.lastname: Hagemann
authors.forename: Susanne
authors.initials: S
authors.lastname: Dollwet-Mack
authors.forename: Elke
authors.initials: E
authors.lastname: Martinez
authors.forename: Tobias
authors.initials: T
authors.lastname: Lohmüller
authors.forename: Gordana
authors.initials: G
authors.lastname: Zlatkovic
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Tobin
authors.forename: Nicole
authors.initials: N
authors.lastname: Maas-Szabowski
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D056668:Cathepsin L; D002403:Cathepsins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005838:Genotype; D006801:Humans; D053547:Keratin-14; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012867:Skin / Q000166:cytology; D013997:Time Factors
chemical_list: C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D004815:Epidermal Growth Factor; D007633:Keratins; D066246:ErbB Receptors; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse