期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 7, 页码 6036-6046出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M406546200
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资金
- NCI NIH HHS [P01-CA98101] Funding Source: Medline
- NIAMS NIH HHS [K08 AR047597, P30 AR057217, K08-AR47597, R01 AR051380] Funding Source: Medline
- NIDDK NIH HHS [P30 DK050306] Funding Source: Medline
The Src-activating and signaling molecule (Srcasm) is a recently described activator and substrate of Src-family tyrosine kinases (SFKs). When phosphorylated at specific tyrosines, Srcasm associates with Grb2 and p85, the regulatory subunit of phosphoinositide 3-kinase; however, little is known about the role of Srcasm in cellular signaling. Data presented here demonstrate that epidermal growth factor (EGF) receptor ligands promote the tyrosine phosphorylation of endogenous and adenovirally transduced Srcasm in keratinocytes, and that increased levels of Srcasm activate endogenous SFKs, with a preference for Fyn and Src. In addition, Srcasm potentiates EGF-dependent signals transmitted by SFKs in keratinocytes. Tyrosine phosphorylation of Srcasm is dependent on growth factors and the activity of EGFR and SFKs. Increased Srcasm expression enhances p44/42 mitogen-activated protein kinase activity and Elk-l-dependent transcriptional events. Elevated Srcasm levels inhibit keratinocyte proliferation while promoting specific aspects of keratinocyte differentiation. Lastly, Srcasm levels are decreased in human cutaneous neoplasia. Collectively, these data demonstrate that Srcasm plays a role in linking EGF receptor- and SFK-dependent signaling to differentiation in keratinocytes.
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