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Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP\u2010dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand\u2010dependent GCC signaling through vasodilator\u2010stimulated phosphoprotein (VASP), an actin\u2010binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP\u2010dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP\u2010dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) actin\u2010based organelles in human colon cancer cells. Membrane organelle disassembly reflected specific phosphorylation of VASP Ser239, the cGMP\/PKG preferred site, and rapid VASP removal from tumor cell protrusions. Importantly, VASP Ser239 phosphorylation inhibited the proteolytic function of invadopodia, reflected by suppression of the cancer cell ability to digest DQ\u2010collagen IV embedded in Matrigel. These results demonstrate a previously unrecognized role for VASP Ser239 phosphorylation, a single intracellular biochemical reaction, as an effective mechanism which opposes tumor cell shape promoting colon cancer invasion and metastasis. Reconstitution of physiological cGMP circuitry through VASP, in turn, represents an attractive targeted approach for patients with colorectal cancer.<\/jats:p>","DOI":"10.1002\/ijc.26257","type":"journal-article","created":{"date-parts":[[2011,6,23]],"date-time":"2011-06-23T13:55:23Z","timestamp":1308837323000},"page":"2539-2548","source":"Crossref","is-referenced-by-count":42,"title":["Phosphorylation of vasodilator\u2010stimulated phosphoprotein Ser239 suppresses filopodia and invadopodia in colon cancer"],"prefix":"10.1002","volume":"130","author":[{"given":"David 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