Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12.
Scaffolding proteins such as SSeCKS/Gravin/AKAP12 ("AKAP12") are thought to control oncogenic signaling pathways by regulating key mediators in a spatiotemporal manner. The downregulation of AKAP12 in many human cancers, often associated with promoter hypermethylation, or the loss of its locus at 6q24-25.2, correlates with progression to malignancy and metastasis. The forced re-expression of AKAP12 in cancer cell lines suppresses in vitro parameters of oncogenic growth, invasiveness, and cell motility through its ability to scaffold protein kinase C (PKC), F-actin, cyclins, Src, and phosphoinositides, and possibly through additional scaffolding domains for PKA, calmodulin, β1,4-galactosyltransferase-polypeptide-1, β2-adrenergic receptors, and cAMP-specific 3',5'-cyclic phosphodiesterase 4D. Moreover, AKAP12 re-expression in tumor models results in metastasis suppression through the inhibition of Src-regulated, VEGF-mediated neovascularization at distal sites. The current review will describe the emerging understanding of how AKAP12 regulates cellular senescence and oncogenic progression at the level of tumor cells and tumor-associated microenvironment via its multiple scaffolding functions.
Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Irwin.gelman@roswellpark.org
Irwin H
IH
Gelman
D054758:A Kinase Anchor Proteins / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D016922:Cellular Senescence; D018450:Disease Progression; D006801:Humans; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D059016:Tumor Microenvironment
D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; D018797:Cell Cycle Proteins