title: Tetraspanin CD82 inhibits protrusion and retraction in cell movement by attenuating the plasma membrane-dependent actin organization.
abstract: To determine how tetraspanin KAI1/CD82, a tumor metastasis suppressor, inhibits cell migration, we assessed which cellular events critical for motility are altered by KAI1/CD82 and how KAI1/CD82 regulates these events. We found that KAI1/CD82-expressing cells typically exhibited elongated cellular tails and diminished lamellipodia. Live imaging demonstrated that the polarized protrusion and retraction of the plasma membrane became deficient upon KAI1/CD82 expression. The deficiency in developing these motility-related cellular events was caused by poor formations of actin cortical network and stress fiber and by aberrant dynamics in actin organization. Rac1 activity was reduced by KAI1/CD82, consistent with the diminution of lamellipodia and actin cortical network; while the growth factor-stimulated RhoA activity was blocked by KAI1/CD82, consistent with the loss of stress fiber and attenuation in cellular retraction. Upon KAI1/CD82 expression, Rac effector cofilin was not enriched at the cell periphery to facilitate lamellipodia formation while Rho kinase exhibited a significantly lower activity leading to less retraction. Phosphatidylinositol 4, 5-biphosphate, which initiates actin polymerization from the plasma membrane, became less detectable at the cell periphery in KAI1/CD82-expressing cells. Moreover, KAI1/CD82-induced phenotypes likely resulted from the suppression of multiple signaling pathways such as integrin and growth factor signaling. In summary, at the cellular level KAI1/CD82 inhibited polarized protrusion and retraction events by disrupting actin reorganization; at the molecular level, KAI1/CD82 deregulated Rac1, RhoA, and their effectors cofilin and Rho kinase by perturbing the plasma membrane lipids.
authors.affiliation: Vascular Biology and Cancer Centers and Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Wei M
authors.initials: WM
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Simon
authors.initials: S
authors.lastname: Moshiach
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.forename: Kamalakkannan
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Seema
authors.initials: S
authors.lastname: Khurana
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
authors.forename: Xin A
authors.initials: XA
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D022081:Cell Surface Extensions / Q000378:metabolism / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D019073:HT29 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051861:Kangai-1 Protein / Q000378:metabolism*; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D022502:Stress Fibers / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; C497688:CD82 protein, human; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D051861:Kangai-1 Protein; D008563:Membrane Lipids; D019269:Phosphatidylinositol 4,5-Diphosphate; C107953:RAC1 protein, human; C066737:RHOA protein, human; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein