The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling.
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.
Reinheckel
Thomas
T
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, 79106 Freiburg, Germany.
Hagemann
Sascha
S
Dollwet-Mack
Susanne
S
Martinez
Elke
E
Lohmüller
Tobias
T
Zlatkovic
Gordana
G
Tobin
Desmond J
DJ
Maas-Szabowski
Nicole
N
Peters
Christoph
C
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
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