Changes in the balance between caldesmon regulated by p21-activated kinases and the Arp2/3 complex govern podosome formation.
Podosomes are dynamic cell adhesion structures that degrade the extracellular matrix, permitting extracellular matrix remodeling. Accumulating evidence suggests that actin and its associated proteins play a crucial role in podosome dynamics. Caldesmon is localized to the podosomes, and its expression is down-regulated in transformed and cancer cells. Here we studied the regulatory mode of caldesmon in podosome formation in Rous sarcoma virus-transformed fibroblasts. Exogenous expression analyses revealed that caldesmon represses podosome formation triggered by the N-WASP-Arp2/3 pathway. Conversely, depletion of caldesmon by RNA interference induces numerous small-sized podosomes with high dynamics. Caldesmon competes with the Arp2/3 complex for actin binding and thereby inhibits podosome formation. p21-activated kinases (PAK)1 and 2 are also repressors of podosome formation via phosphorylation of caldesmon. Consequently, phosphorylation of caldesmon by PAK1/2 enhances this regulatory mode of caldesmon. Taken together, we conclude that in Rous sarcoma virus-transformed cells, changes in the balance between PAK1/2-regulated caldesmon and the Arp2/3 complex govern the formation of podosomes.
Morita
Tsuyoshi
T
Department of Neuroscience (D13), Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
Mayanagi
Taira
T
Yoshio
Toshiyuki
T
Sobue
Kenji
K
D051377:Actin-Related Protein 2 / Q000378:metabolism*; D051378:Actin-Related Protein 3 / Q000378:metabolism*; D000199:Actins / Q000737:chemistry; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D052736:Rous sarcoma virus / Q000378:metabolism; D014162:Transfection; D014335:Tropomyosin / Q000737:chemistry; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000737:chemistry; D054462:p21-Activated Kinases
D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; D002148:Calmodulin-Binding Proteins; D014335:Tropomyosin; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C515906:Pak1 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases