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Vol. 16, Issue 7, 3236-3246, July 2005

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Calcium-induced Human Keratinocyte Differentiation Requires src- and fyn-mediated Phosphatidylinositol 3-Kinase–dependent Activation of Phospholipase C-1

Endocrine Unit, Veterans Affairs Medical Center, Northern California Institute for Research and Education and University of California–San Francisco, San Francisco, CA 94121

Submitted February 10, 2005; Revised April 11, 2005; Accepted April 25, 2005
Monitoring Editor: M. Bishr Omary

We have previously demonstrated that phospholipase C (PLC)-1 is required for calcium-induced human keratinocyte differentiation. In the present study, we investigated whether the activation of PLC-1 by nonreceptor kinases such as src and fyn plays a role in mediating this process. Our results showed that the combination of dominant negative src and fyn blocked calcium-stimulated PLC-1 activity and human keratinocyte differentiation, whereas each separately has little effect. However, unlike the activation of PLC-1 by epidermal growth factor, calcium-induced activation of PLC-1 was not a result of direct tyrosine phosphorylation. Therefore, we examined an alternative mechanism, in particular phosphatidylinositol 3,4,5-triphosphate (PIP₃) formed as a product of phosphatidylinositol 3-kinase (PI3K) activity. PIP₃ binds to and activates PLC-1. The combination of dominant negative src and fyn blocked calcium-induced tyrosine phosphorylation of the regulatory subunit of PI3K, p85, and the activity of the catalytic subunit of PI3K. PI3K inhibitors blocked calcium activation of PLC-1 as well as the induction of keratinocyte differentiation markers involucrin and transglutaminase. These data indicate that calcium activates PLC-1 via increased PIP₃ formation mediated by c-src– and fyn-activated PI3K. This activation is required for calcium-induced human keratinocyte differentiation.

Abbreviations used: DAG, diacylglycerol; EGF, epidermal growth factor; IP₃, inositol 1,4,5-trisphosphate; KGM, keratinocyte growth medium; PI3K, phosphatidylinositol 3-kinase; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-bisphosphate; PLC, phospholipase C.

Address correspondence to: Zhongjian Xie (zjxie{at}itsa.ucsf.edu).

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