Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12

Abstract

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.

Expression array analysis of the hepatocyte growth factor invasive program

“…Like E-cadherin, P-cadherin (CDH3) expression promoted cell-cell adhesion and countered invasion in melanoma [96], oral squamous cell carcinoma [97] and breast cancer model systems [98]; HGF ligands suppressed CDH3 in PC3M, suggesting release from this negative regulator consistent with enhanced invasion. Similarly, the adhesion adapter AKAP12 repressed prostate metastasis and cell motility by sequestering Src away from FAK-associated adhesion and signaling complexes [99][100][101], suggesting that AKAP12 suppression by HGF ligands is likely to promote PC3M invasion and metastasis. HGF-suppression of the protein tyrosine phosphatase encoded by PTPRM, a negative regulator of invasion by glioma [102] and breast cancer [103] cells, and upregulation of the integrin adapter encoded by NEDD9, which promotes epithelial-to-mesenchymal transition and invasion by PCa cells [104,105], also predict enhancement of PC3M invasiveness.…”

Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell’s Journey

“…Following crosslinking to the actin cytoskeleton and plasma membrane, SSeCKs translocates and correspondingly transports macromolecules such as Src, PKC, PKA, Factin, calmodulin, cyclins and phospholipids to other organelles. SSeCKS re-expression decreases invasion and invadosome formation by disengaging Src from activating downstream RhoGTPase and/or PKC-Raf/MEK/ ERK-mediated pathways which, in turn, control MMP expression [97][98][99].…”

“…Gelman and colleagues have shown that SSeCKS re-expression in rat prostate cancer cells reduces metastasis by affecting neovascularization at distal sites, but not by inhibiting tumor cell motility or proliferation [97,100,101]. Using a spontaneous metastasis model, Akakura et al showed that B16F10 melanoma cells developed significantly more metastases in SSeCKS-null mice with no difference on primary tumor growth [102].…”

MicroRNA-186 and metastatic prostate cancer.

“…Six out of seven published reports indicate AKAP12 plays a role in cell proliferation [145,152,[156][157][158][159][160]. Early passaged AKAP12 -/-or knock out MEFs cells exhibited a higher cellular proliferation than wild type MEFs [158].…”

“…Only a select number of miR-186 targets (p53, PTEN, CASP9, FOXO3, AKAP12, PTEN, TRIB3, IL1RL1) AKAP12 (A-kinase anchor protein 12) also known as the mouse homolog SSecKS functions as a scaffold protein in signal transduction that associates with protein kinases A (PKA) and C and phosphatase [152].…”