The phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway has recently emerged as a major target for regulation by caveolin-1 in a variety of cancer cells [12,13,86]. A possible role of caveolin-1 in PI3K/Akt pathway activation was shown in multiple myeloma cells which, unlike most other hematopoietic-derived cells, express high levels of caveolin-1 . Caveolin-1 was found to co-localize in lipid rafts fractions, and to co-exist in an immunoprecipitable complex, with receptors for insulin-like growth factor-I (IGF-I) and interleukin-6 (IL-6). These cell survival-inducing factors stimulated c-Src-mediated phosphorylation of caveolin-1 on Tyr14 and its association with PI3K subunits. The disruption of lipid raft organization by cholesterol depletion resulted in a redistribution of caveolin-1 and PI3K, an inhibition of Tyr14 phosphorylation of caveolin-1, and an abrogated IGF-I- and IL-6-induced activation of Akt and survival, thus confirming that both caveolin-1 and intact caveolae are essential for these processes . Consistent with this conclusion, transient expression of caveolin-1 in LNCaP human prostate cancer cells resulted in elevated Akt phosphorylation and activation and increased resistance to thapsigargin-induced apoptosis . Similarly, stable expression of caveolin-1 in MCF-7 human breast cancer cells also resulted in elevated basal phosphorylation of Akt, concomitantly increasing cellular resistance to anoikis .
Interestingly, a correlation between caveolin-1 expression and Akt activation was also seen in HEK-293 human embryonic kidney cells  and L929 mouse fibrosarcoma cells  although, in the latter two cases, Akt activation was reported to sensitize the cells to the apoptotic stimuli.
The mechanisms whereby caveolin-1 regulates PI3K/Akt-mediated cell survival have yet to be fully elucidated. It is clear, however, that caveolin-1 may influence this important pathway by recruiting and/or modulating its various components at different levels. First, caveolin-1 may act at the receptor level, as shown in caveolin-1-expressing MCF-7 cells, in which IGF-I receptor expression is elevated . In these cells, the up-regulation of IGF-I receptors is associated with enhanced IGF-I signaling to the Erk1/2 and PI3K/Akt pathways (Fig. 12.1). In endothelial cells, caveolin-1 promotes the nongenomic action of nuclear receptors such as the estrogen receptor-a (ERa), resulting in activation of Akt and endothelial nitric oxide synthase (eNOS) . Whether a similar mechanism operates in steroid-dependent human cancers, such as breast cancer and prostate cancer, has yet to be determined. In endothelial cells, caveolin-1 similarly interacts with TNF-a receptors,
blotted with antibodies to the active phos-pho-Erk1/2 (pErk1/2), Erk1/2, phospho-Akt (pAkt) and actin (loading control) as indicated. (Figure reprinted, with permission, from .)
allowing TNF-a-induced activation of Akt . An essential role of caveolin-1 in avp3 integrin-dependent activation of PI3K and Akt upon mechanical stress was recently noted also in VSMC . In these cells, caveolin-1 is additionally required for angiotensin II receptor transactivation of the EGF receptor after Racl and NADPH oxidase activation, resulting in Akt activation . Caveolin-1 is part of a survival signaling complex comprising urokinase-type plasminogen activator receptor, integrin avp3/a5p1 and the SFK Yes in vitronectin-attached endothelial cells .
As mentioned above, caveolin-1 recruits both regulatory and catalytic subunits of PI3K upon IGF-I and IL-6 stimulation in multiple myeloma cells . Phosphoino-sitide-dependent protein kinase-1 (PDK1), which mediates Akt Thr308 phosphorylation was also found physically to interact with caveolin-1 . However, in this case a caveolin-1 scaffolding peptide suppressed the self-phosphorylation and the in-vitro kinase activities of PDK1. These results are inconsistent with the data showing that caveolin-1 significantly increases the activity of PDK1 and Akt . Chun and co-workers suggested that these differences may result from changes in both subcellular localization and in the affinity to caveolin-1 of PDK1 compared to other factors (such as the serine/threonine protein phosphatases) . Integrin-linked kinase has been proposed to serve as an Akt Ser473-kinase, and was found to interact with caveolin-1 via a CSD-binding motif [93,94]. Intriguingly, another putative Akt Ser473 kinase, namely DNA-PK, is localized in part in lipid rafts, although in this case direct interaction with caveolin-1 has yet to be demonstrated .
Finally, caveolin-1 may regulate the PI3K/Akt pathway by affecting lipid and protein phosphatases that turn the pathway off. Interaction of caveolin-1 via its CSD with protein phosphatases that dephosphorylate phospho-Akt, namely PP1 and PP2A, results in their inhibition and in consequent activation of Akt in LNCaP
cells . Caveolin-1 is also associated with the tumor suppressor protein PTEN, a 3-phosphoinositide phosphatase that terminates the PI3K-dependent signal, although in this case the effect of caveolin-1 on PTEN activity has not been determined . Interestingly, it was shown recently that caveolin-1 knockout up-reg-ulates PTEN expression in TRAMP mouse prostate tumors, consistent with the inhibition of tumor progression caused by loss of caveolin-1 in this model .
The PI3K/Akt pathway is not the only survival pathway that is regulated by caveolin-1. Although caveolin-1 usually inhibits growth factor activation of the mitogenic Erk1/2 pathway, it is required for integrin-dependent activation of Erk1 / 2 through a complex that consists of Fyn, Shc, and Grb2 [97,98]. The Erk1/2 pathway promotes cell survival, at least in some cell types [99,100]. Caveolin-1 is similarly required for p1-integrin-mediated signaling to Src kinases and focal adhesion kinase (FAK) and, consequently, b1-integrin-dependent adhesion . Caveolin-1 enables activation of c-Src upon cross-linking of the cell adhesion protein CE-CAM6 in BxPC3 human pancreatic adenocarcinoma cells, as well as c-Src-depend-ent tyrosine phosphorylation of FAK and the consequent inhibition of anoikis . A positive regulatory role of caveolin-1 on survival signaling may also be implied by data showing that it interacts with a component of the TNF-a-NFkB pathway , and that it may inhibits a caveolae-resident neutral sphingomyelinase via its CSD sequence .
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