Tyr14 resides within a consensus motif for c-Src and c-Abl phosphorylation, present in caveolin-1a (but not in caveolin-1b), that is phosphorylated in a constitutive manner in v-Src- and v-Abl-transformed cells [16,104,105]. Phosphorylation of Tyr14 in response to cell stimulation has emerged recently as a major switch in caveolin-1 physiological function. Tyr14 phosphorylation occurs in various cell types in response to extracellular signal molecules such as insulin , IGF-I , EGF , fibronectin , IL-6 , PDGF , VEGF , and adrenocorticotropic hormone (ACTH) . In addition, Tyr14 phosphorylation occurs in response to cell stressors such as oxidants , hyperosmolarity and UV irradiation , DNA damage-inducing drugs , and denial of extracellular matrix attachment .
Although insulin-dependent Tyr14 phosphorylation was initially believed to be mediated by a Src-family kinase (SFK) , more recent studies have shown that insulin-dependent Tyr14 phosphorylation is insensitive to a general SFK inhibitor, and suggested instead that it is mediated by the insulin receptor directly . In contrast, EGF-, IGF-I and IL-6-induced phosphorylation of Tyr14 were inhibited by the same SFK blocker [86,118]. Similarly, a SFK is clearly involved in hyperosmotic stress-induced Tyr14 phosphorylation, since it is strongly inhibited by a dominantnegative form of Src . As noted above, exposure of primary human fibroblasts to oxidative stress causes Tyr14 phosphorylation, and the SFK Fyn was shown to be required for this response . In the same cells, this phosphorylation event also depends on the presence of c-Abl . The relationship between Fyn- and Abl-mediated phosphorylation of caveolin-1 is unclear, as both are required for oxidant-induced Tyr14 phosphorylation, but neither kinase is required for the action of the other, suggesting that Fyn and Abl do not participate in a linear signaling pathway . It was proposed that low level of oxidative stress results in the activation of Fyn and Tyr14 phosphorylation, promoting cell survival, whereas Abl is activated (and phosphorylates caveolin-1) upon high level of oxidant exposure, leading to apoptosis .
What is the role of the phosphorylation of caveolin on Tyr14? The formation of a phosphotyrosine residue likely constitutes a binding site for proteins with Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains. Such proteins, recruited upon Tyr14 phosphorylation, include Grb7  and Csk [121,122]. The recruitment of Grb7 to pTyr14 was shown to greatly enhance anchorage-independent growth in cells co-transfected with Grb7, c-Src, and caveolin-1 . Similarly, caveolin-1 transfection markedly increased EGF-stimulated cell migration and this, too, was dependent on the presence of a phosphorylatable Tyr14 . The recruitment of Csk, which catalyzes the C-terminal phosphorylation of SFK and inhibits their activity, is likely a part of a negative regulatory loop wherein Csk limits or abrogates SFK activation in oxidant-stressed cells . In accordance with this study, crosslinking of the GPI-anchored protein CECAM6 reduced caveolin-1 Tyr14 phosphorylation, forcing its dissociation from the Csk and thus inducing Src-dependent activation of FAK . Recently, Tyr14 phosphorylation was found to mediate interaction of caveolin-1 with the membrane type I matrix metal-loprotease and this interaction, in turn, was shown to correlate with the protease-induced cell migration . This interesting finding resonates with the fact that pTyr14-caveolin-1 is localized in focal adhesions, as shown in Src-transfected cells [105,124], as well as cells exposed to hyperosmotic and oxidative stress [114,120], cells plated on a fibronectin matrix [109,122,124], and cells treated with ACTH . In summary, although the precise mechanisms and role of Tyr14 phosphorylation has not been fully resolved, the evidence accumulated so far clearly implicates this event as critical to at least some of the physiological functions of caveolin-1. In this context, of particular interest are the differential actions of caveolin-1a and caveolin-1 b, which could be related to the lack of the Tyr14 residue in the latter protein.
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