The Role of Caveolin Phosphorylation in Cells

Our current hypothesis is that caveolin organizes signaling complexes containing Fyn, Csk, and Abl that regulate cortical actin remodeling. Caveolin phosphorylation is required for the recruitment of both Csk and Abl into the complexes, which leads to negative regulation of the Src-family kinases that are resident in the caveolae. When the phosphorylation of caveolin is catalyzed by the Src-kinases themselves, this is a mechanism for the transient activation/rapid Csk-induced attenuation of Src-kinases through feedback inhibition. When the caveolin is phosphorylated by Abl, this regulatory mechanism would inhibit activation of a specific pool of Src family kinases. This regulatory complex involves the following three steps (Fig. 6.7):

Caveolae Actin
Fig. 6.7 Caveolin organizes signaling complexes with Fyn, Csk and Abl that regulate cortical actin remodeling.

1. Insulin or stress activates Fyn that is resident in the caveolae. This leads to the phosphorylation of specific Fyn substrates involved in focal adhesion turnover, cell migration, and cell survival.

2. It also leads to the phosphorylation of caveolin-1 at Tyr14. Caveolin phosphor-ylation recruits Csk, which attenuates Fyn activity. The transient activation of Fyn allows for the transient release of actin from the plasma membrane. Fyn must be then be inactivated to allow subsequent reformation of actin contact sites.

3. Prolonged signals activate/recruit Abl, leading to high-level, sustained phosphorylation of caveolin and sustained attenuation of Fyn. This leads to inhibi tion of focal adhesion turnover and inhibition of cell migration, stabilization of actin, and can lead to apoptosis.

This model links caveolin phosphorylation to two pathways known to be impacted by caveolin expression: actin assembly/cell migration and control of cell growth.

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