Receptor tyrosine phosphatase–dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4

Abstract

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 RPTPδ and, in turn, enhances RPTPδ membrane localization. MIM-dependent cytoskeletal changes can be inhibited using a soluble RPTPδ-D2 domain. Our data suggest that the hedgehog-responsive gene MIM cooperates with RPTP to induce cytoskeletal changes.

Tyrosine Phosphorylation of Missing in Metastasis Protein Is Implicated in Platelet-derived Growth Factor-mediated Cell Shape Changes

“…Tyrosine phosphorylation of endogenous Mtss1 was analyzed by immunoprecipitation with Mtss1 followed by phosphotyrosine immunoblot. Consistent with our previous report and others (16,17,19), endogenous Mtss1 is resolved as two bands, with the major one at a position near 115 kDa (Fig. 4C, right panel).…”

“…However, how MTSS1 induces these changes is not understood. MTSS1 has been proposed to be a scaffolding protein by linking F-actin to other intracellular proteins, including Rac1 (16) and ␦ type receptor protein tyrosine phosphatases (15,17). On the other hand, the potential of MTSS1 to act as a signaling protein has also been evidenced.…”

“…Although the relevance of such down-regulation to tumor progression, in particular, metastasis, has not yet been confirmed, several lines of evidence have indicated a role of MTSS1 in cell morphogenesis. Overexpression of MTSS1 triggers distinct cell shape changes such as increase in the formation of lamellipodia, membrane ruffles, and filopodia-like structures (5,12,(15)(16)(17). More interestingly, MTSS1 has been found to be a target of Sonic hedgehog, a well characterized morphogen that plays a critical role in the patterning of embryonic and adult tissues (18).…”

Allelic imbalances and microdeletions affecting the PTPRD gene in cutaneous squamous cell carcinomas detected using single nucleotide polymorphism microarray analysis

“…Using 10K SNP microarray analysis all microdeletions were mapped to a region spanning 8.45-11.0 Mb, within the locus of the recently identified PTPRD (protein tyrosine phosphatase receptor type D) L isoform (Sato et al, 2005). The physiological function of PTPRD has not been fully characterized, although it is known to interact with the putative metastasis suppressor protein MIM to mediate actin cytoskeletal reorganization (Gonzalez-Quevedo et al, 2005). To date, a tumor suppressor role for PTPRD remains speculative, although several other protein tyrosine phosphatase receptors have been postulated as tumor suppressor genes including PTPRO in lung cancer (Motiwala et al, 2004) and HPTPη, implicated in several carcinomas, most recently pancreatic cancer (Trapasso et al, 2004).…”

Receptor Tyrosine Phosphatases Guide Vertebrate Motor Axons during Development

“…Additionally, LAR interacts with the guanine nucleotide exchange factor Trio, which can activate Rho family GTPases to regulate actin filaments (Bixby, 2001;Johnson and Van Vactor, 2003). A recent paper shows that PTP-␦ interacts with an actin-binding protein called MIM in fibroblasts, suggesting that cytoskeletal interactions are common to type IIa RPTPs (Gonzalez-Quevedo et al, 2005). The type IIa and type III RPTPs could have opposing effects on the same signaling pathway, or affect opposing signaling pathways, to control cytoskeletal rearrangements in the growth cone.…”