A wide variety of soluble signaling substances utilize the cyclic AMP-dependent protein kinase (PKA) pathway to regulate cellular behaviors including intermediary metabolism, ion channel conductivity, and transcription. A growing literature suggests that integrin-mediated cell adhesion may also utilize PKA to modulate adhesion-associated events such as actin cytoskeletal dynamics and migration. PKA is dynamically regulated by integrin-mediated cell adhesion to extracellular matrix (ECM). Furthermore, while some hallmarks of cell migration and cytoskeletal organization require PKA activity (e.g. activation of Rac and Cdc42; actin filament assembly), others are inhibited by it (e.g. activation of Rho and PAK; interaction of VASP with the c-Abl tyrosine kinase). Also, cell migration and invasion can be impeded by either inhibition or hyper-activation of PKA. Finally, a number of A-kinase anchoring proteins (AKAPs) serve to associate PKA with various components of the actin cytoskeleton, thereby enhancing and/or specifying cAMP/PKA signaling in those regions. This review discusses the growing literature that supports the hypothesis that PKA plays a central role in cytoskeletal regulation and cell migration.
Mitochondria infiltrate leading edge lamellipodia, increasing local mitochondrial mass and relative ATP concentration. AMPK regulates infiltration of mitochondria into the leading edge of 2D lamellipodia and 3D invadopodia, coupling local metabolic sensing to subcellular targeting of mitochondria during cell movement.
Activation of the canonical mitogen-activated protein kinase (MAPK) cascade by soluble mitogens is blocked in non-adherent cells. It is also blocked in cells in which the cAMP-dependent protein kinase (PKA) is activated. Here we show that inhibition of PKA allows anchorage-independent stimulation of the MAPK cascade by growth factors. This effect is transient, and its duration correlates with sustained tyrosine phosphorylation of paxillin and focal-adhesion kinase (FAK) in non-adherent cells. The effect is sensitive to cytochalasin D, implicating the actin cytoskeleton as an important factor in mediating this anchorage-independent signalling. Interestingly, constitutively active p21-activated kinase (PAK) also allows anchorage-independent MAPK signalling. Furthermore, PKA negatively regulates PAK in vivo, and whereas the induction of anchorage-independent signaling resulting from PKA suppression is blocked by dominant negative PAK, it is markedly prolonged by constitutively active PAK. These observations indicate that PKA and PAK are important regulators of anchorage-dependent signal transduction.
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