title: Phosphorylation of vasodilator-stimulated phosphoprotein Ser239 suppresses filopodia and invadopodia in colon cancer.
abstract: In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) actin-based 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-collagen 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Zuzga
authors.forename: Joshua
authors.initials: J
authors.lastname: Pelta-Heller
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bombonati
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
authors.forename: Giovanni M
authors.initials: GM
authors.lastname: Pitari
mesh_terms: D015815:Cell Adhesion Molecules / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D022081:Cell Surface Extensions / Q000473:pathology*; D024141:Collagen Type IV / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology*; D006162:Guanylate Cyclase / Q000502:physiology; D006801:Humans; D008840:Microfilament Proteins / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D024141:Collagen Type IV; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D006162:Guanylate Cyclase