A‐kinase anchoring proteins: From protein complexes to physiology and disease

Abstract

SummaryProtein scaffold complexes are a key mechanism by which a common signaling pathway can serve many different functions. Sequestering a signaling enzyme to a specific subcellular environment not only ensures that the enzyme is near its relevant targets, but also segregates this activity to prevent indiscriminate phosphorylation of other substrates. One family of diverse, well-studied scaffolding proteins are the A-kinase anchoring proteins (AKAPs). These anchoring proteins form multi-protein complexes that integrate cAMP signaling with other pathways and signaling events. In this review, we focus on recent advances in the elucidation of AKAP function.

SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

“…Taken together, these results demonstrate that in the absence of SSeCKS scaffolding function, PECs develop a markedly exaggerated and detrimental proliferative response to mitogenic injury in vivo. 9,10 These results also highlight the critical role of tumor suppressors to properly maintain niches of tissue progenitor cells. 6 However, as with other G 1 -to-S cell-cycle inhibitors, 8 absence of SSeCKS does not appear to be sufficient alone to induce clinical glomerular disease.…”

“…Notably, however, unlike the loss of SSeCKS expression and scaffolding function that occurs in malignancies from genetic deletion of ssecks/akap12, 9 our staining of podocytopathy models containing ssecks/akap12 shows that SSeCKS expression remains in PECs forming non-malignant extracapillary lesions. Thus, the cyclic, temporal loss of SSeCKS scaffolding function in proliferating PECs in diseased glomeruli likely occurs by its rapid phosphorylation and de-phosphorylation, as known for AKAPs, 10 which we cannot detect in vivo with our current reagents. In any respect, our results extend that of others suggesting that diseased PECs may play an important role in determining the morphology and clinical outcome following glomerular injury, [3][4][5] with SSeCKS being one newly identified determinant of the cellular response by PECs.…”

“…9,10 For example, by scaffolding and attenuating PKCa/d, SSeCKS suppresses pathways that induce senescence, 35 a 'care-taking' role of some tumor suppressors to maintain niches of tissue progenitors. 6 This would be a rationale function for SSeCKS in PECs, which theoretically must continually self-renew without aging to replace podocytes throughout life.…”

“…SSeCKS is a cytoplasmic, multivalent scaffolding protein in the family of A kinase anchoring proteins (AKAPs) 10 that was originally cloned as a tumor suppressor. 11,12 SSeCKS is unique among AKAPs by containing protein kinase C (PKC) phosphorylation sites that flank cyclin-binding motifs, which bind cyclin D1.…”

Enzyme localization, crowding, and buffers collectively modulate diffusion-influenced signal transduction: Insights from continuum diffusion modeling

“…This raises the possibility that the kinetics of biochemical reactions may be in part controlled by the cellular environment through its interaction with diffusing substrates, in complement to more direct modulation of enzyme expression or activity. As such, our findings are directly applicable to biomolecular signaling pathways that exploit enzyme localization and compartmentation, including sodium handling, 63 A-kinase anchoring protein-coupled cyclic AMP signaling, 64 as well as metabolically linked ion channels, like the ATP-dependent potassium channel. 40 While ordinary and time-delay differential equation models provide means to qualitatively demonstrate these phenomena, explicit consideration of the barrier's spatial attributes via partial differential equations permits quantitative assessments using measurable physiological quantities, such as protein localization and crowder composition.…”