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PKA
A major function of cAMP in eukaryotes is the activation of PKA. cAMP acts in mammalian cells by binding to two distinct isoforms of PKA, defined PKA-I and PKA-II. PKA-I and PKA-II differ in regulatory (R) subunits, termed RI in PKA-I and RII in PKA-II, respectively. PKA holoenzymes are inactive heterotetramers. Binding of two cAMP molecules to each of the regulatory subunits results in the release and activation of the catalytic subunits. The major nuclear targets of PKA are the transcription factors of the cAMP response element binding (CREB) family. CREB proteins bind optimally to palindromic CREs (sequence TGACGTCA) in promoters and upon phosphorylation by PKA they recruit the coactivator, CREB binding protein (CBP) to the promoter. Such a phosphorylation event results in the induction of cellular gene expression. cAMP/PKA signaling pathway is altered in different cancers and may be exploited for cancer therapy and/or diagnosis. Low cAMP levels are detected at mitosis, while higher levels are present in G1 and early S; on the other hand, PKA phosphorylates macromolecular complexes responsible for the destruction of mitotic cyclins and separation of the sister chromatids at anaphase-metaphase transition.
PKA may act synergistically with Epac to induce mitogenesis in endocrine cells. By modulating the timing and localization of cAMP production, it is possible to affect the activation of PKA (and also of other cAMP effectors), that in turn can act on the RAS/ERK and/or other signaling pathways, involved in cell cycle progression. PKA catalytic ß subunit has been shown to be a direct transcriptional target of c-MYC, and proposed as a crucial component of the program by which constitutive c-MYC expression contributes to cell transformation. In MDA-MB-231 breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1/2 and STAT3 phosphorylation in response to leptin, strongly lowers protein levels of both regulatory RIa and catalytic subunits of PKA, with a consistent reduction of CREB phosphorylation, and inhibits both leptin-induced proliferation and migration. PKA may operate and may be dysregulated in cancer, is the actin-based cell migration, that involves cytoskeleton remodeling. PKA regulates actin dynamics, by targeting structural proteins, like actin, integrins, VASP and myosin light chain, and regulatory proteins, like Rho GTPases, Src kinases, p21-activated kinases, phosphatases and proteases.
References
1.Sapio L,et al. EXCLI J. 2014;13:843–855.
PKA may act synergistically with Epac to induce mitogenesis in endocrine cells. By modulating the timing and localization of cAMP production, it is possible to affect the activation of PKA (and also of other cAMP effectors), that in turn can act on the RAS/ERK and/or other signaling pathways, involved in cell cycle progression. PKA catalytic ß subunit has been shown to be a direct transcriptional target of c-MYC, and proposed as a crucial component of the program by which constitutive c-MYC expression contributes to cell transformation. In MDA-MB-231 breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1/2 and STAT3 phosphorylation in response to leptin, strongly lowers protein levels of both regulatory RIa and catalytic subunits of PKA, with a consistent reduction of CREB phosphorylation, and inhibits both leptin-induced proliferation and migration. PKA may operate and may be dysregulated in cancer, is the actin-based cell migration, that involves cytoskeleton remodeling. PKA regulates actin dynamics, by targeting structural proteins, like actin, integrins, VASP and myosin light chain, and regulatory proteins, like Rho GTPases, Src kinases, p21-activated kinases, phosphatases and proteases.
References
1.Sapio L,et al. EXCLI J. 2014;13:843–855.
