期刊
JOURNAL OF CELL BIOLOGY
卷 162, 期 7, 页码 1189-1196出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200305006
关键词
keratinocyte; proliferation; palmitoylation; hemidesmosome; cysteine
类别
资金
- NCI NIH HHS [R37 CA058976, P30 CA008748, R37 CA58976, P30 CA08748] Funding Source: Medline
- NIGMS NIH HHS [R01 GM057966, R01 GM57966] Funding Source: Medline
Integrin alpha6beta4 signaling proceeds through Src family kinase (SFK)-mediated phosphorylation of the cytoplasmic tail of beta4, recruitment of Shc, and activation of Ras and phosphoinositide-3 kinase. Upon cessation of signaling, alpha6beta4 mediates assembly of demidesmosomes. Here, we report that part of alpha6beta4 is incorporated in lipid rafts. Metabolic labeling in combination with mutagenesis indicates that one or more cysteine in the membrane-proximal segment of beta4 tail is palmitoylated. Mutation of these cysteines suppresses incorporation of alpha6beta4 in lipid rafts, but does not affect alpha6beta4-mediated adhesion or assembly of hemidesmosomes. The fraction of alpha6beta4 localized to rafts associates with a palmitoylated SFK, whereas the remainder does not. Ligation of palmitoylation-defective alpha6beta4 does not activate SFK signaling to extracellular signal-regulated kinase and fails to promote keratinocyte proliferation in response to EGF. Thus, compartmentalization in lipid rafts is necessary to couple the alpha6beta4 integrin to a palmitoylated SFK and promote EGF-dependent mitogenesis.
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