Receptor tyrosine phosphatase-dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4.
During development, dynamic remodeling of the actin cytoskeleton allows the precise placement and morphology of tissues. Morphogens such as Sonic hedgehog (Shh) and local cues such as receptor protein tyrosine phosphatases (RPTPs) mediate this process, but how they regulate the cytoskeleton is poorly understood. We previously identified Basal cell carcinoma-enriched gene 4 (BEG4)/Missing in Metastasis (MIM), a Shh-inducible, Wiskott-Aldrich homology 2 domain-containing protein that potentiates Gli transcription (Callahan, C.A., T. Ofstad, L. Horng, J.K. Wang, H.H. Zhen, P.A. Coulombe, and A.E. Oro. 2004. Genes Dev. 18:2724-2729). Here, we show that endogenous MIM is induced in a patched1-dependent manner and regulates the actin cytoskeleton. MIM functions by bundling F-actin, a process that requires self-association but is independent of G-actin binding. Cytoskeletal remodeling requires an activation domain distinct from sequences required for bundling in vitro. This domain associates with RPTPdelta and, in turn, enhances RPTPdelta membrane localization. MIM-dependent cytoskeletal changes can be inhibited using a soluble RPTPdelta-D2 domain. Our data suggest that the hedgehog-responsive gene MIM cooperates with RPTP to induce cytoskeletal changes.
Gonzalez-Quevedo
Rosa
R
Program in Epithelial Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Shoffer
Marina
M
Horng
Lily
L
Oro
Anthony E
AE
D000199:Actins / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000187:drug effects / Q000502:physiology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000737:chemistry; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D022001:Focal Adhesions / Q000737:chemistry; D019922:GAP-43 Protein / Q000235:genetics; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000032:analysis; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000032:analysis; D016716:PC12 Cells; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014157:Transcription Factors; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014638:Vanadates / Q000494:pharmacology
D000199:Actins; D019922:GAP-43 Protein; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; C473219:Mtss1 protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D019269:Phosphatidylinositol 4,5-Diphosphate; D011506:Proteins; C000606240:Ptch1 protein, mouse; C000606239:Ptch1 protein, rat; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D014638:Vanadates; D017027:Protein Tyrosine Phosphatases; C490395:Ptprd protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2