title: WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility.
abstract: We previously identified Waf1 Cip1 stabilizing protein 39 (WISp39) as a binding partner for heat shock protein 90 (Hsp90). We now report that WISp39 has an essential function in the control of directed cell migration, which requires WISp39 interaction with Hsp90. WISp39 knockdown (KD) resulted in the loss of directional motility of mammalian cells and profound changes in cell morphology, including the loss of a single leading edge. WISp39 binds Coronin 1B, known to regulate the Arp2/3 complex and Cofilin at the leading edge. WISp39 preferentially interacts with phosphorylated Coronin 1B, allowing it to complex with Slingshot phosphatase (SSH) to dephosphorylate and activate Cofilin. WISp39 also regulates Arp2/3 complex localization at the leading edge. WISp39 KD-induced morphological changes could be rescued by overexpression of Coronin 1B together with a constitutively active Cofilin mutant. We conclude that WISp39 associates with Hsp90, Coronin 1B, and SSH to regulate Cofilin activation and Arp2/3 complex localization at the leading edge.
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors: Michael
authors: M
authors: Howell
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors: Howard
authors: H
authors: Brickner
authors: The Scripps Research Institute, La Jolla, CA 92037.
authors: Violaine D
authors: VD
authors: Delorme-Walker
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors: Justin
authors: J
authors: Choi
authors: Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037.
authors: Jean-Michel
authors: JM
authors: Saffin
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors: Daniel
authors: D
authors: Miller
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors: Andreas
authors: A
authors: Panopoulos
authors: The Scripps Research Institute, La Jolla, CA 92037.
authors: Céline
authors: C
authors: DerMardirossian
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors: Arun
authors: A
authors: Fotedar
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors: Robert L
authors: RL
authors: Margolis
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037 rfotedar@sanfordburnham.org.
authors: Rati
authors: R
authors: Fotedar
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020104:Immunophilins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D022021:Tacrolimus Binding Proteins
chemical_list: D051339:Actin Depolymerizing Factors; D051376:Actin-Related Protein 2-3 Complex; C400101:FKBPL protein, human; D018841:HSP90 Heat-Shock Proteins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; C072061:coronin proteins; D010749:Phosphoprotein Phosphatases; C525231:slingshot phosphatase 2, human; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins