Mystique Is a New Insulin-like Growth Factor-I-regulated PDZ-LIM Domain Protein That Promotes Cell Attachment and Migration and Suppresses Anchorage-independent Growth

Abstract

By comparing differential gene expression in the insulin-like growth factor (IGF)-IR null cell fibroblast cell line (R؊ cells) with cells overexpressing the IGF-IR (R؉ cells), we identified the INTRODUCTIONInsulin-like growth factor (IGF)-I and IGF-II are ligands for the widely expressed IGF-I receptor tyrosine kinase, which promotes mitogenesis and cell survival (reviewed in Adams et al., 2000). The IGF-IR is essential for normal growth during embryonic development and promotes cell survival and migration. Circulating IGFs and the IGF-IR signaling pathways also have been associated with cancer progression (reviewed in LeRoith and Roberts, 2003). In a mouse model of pancreatic islet cell tumorigenesis, endogenous IGF-IR expression was up-regulated at invasive regions of the tumors, and ectopic IGF-IR expression resulted in the accelerated development of highly invasive and metastatic carcinomas (Lopez and Hanahan, 2002). Conversely, the suppression of IGF-IR expression by antisense strategies (Resnicoff, 1998) or blocking antibodies results in decreased tumor growth and decreased metastatic capacity in tumor cell models (Maloney et al., 2003). Signals from the IGF-IR associated with survival, tumorigenicity, and metastasis are associated with the C terminus of the receptor (O'Connor et al., 1997;Brodt et al., 2001;Baserga et al., 2003).Cell migration and invasion are complex processes that require the coordination of signals from both adhesion and growth factor receptors. Signals from the IGF-IR can interact with those from integrins to initiate the formation of signaling complexes necessary for the formation and disassembly of cell adhesions with the extracellular matrix (ECM) (Doerr and Jones, 1996;Brooks et al., 1997). These signals involve enhancement of Shc phosphorylation (Mauro et al., 1999;Jackson et al., 2000;Kim et al., 2004), regulation of focal adhesion kinase phosphorylation at focal adhesions (Manes et al., 1999), differential regulation of signals by scaffolding proteins such as RACK1 (Hermanto et al., 2002;Kiely et al., 2002), signals from reorganization of the cytoskeleton (Casamassima and Rozengurt, 1998;Kim and Feldman, 1998;Guvakova et al., 2002), expression of angiogenic and invasive factors , regulation of cadherin location (Playford et al., 2000;Pennisi et al., 2002), and transactivation of the epidermal growth factor (EGF) receptor (Burgaud and Baserga, 1996;Roudabush et al., 2000). How all of these events are coordinated during cell migration or invasion, or how some of these signals are enhanced in metastatic cancer, is still poorly understood.IGF-I induces expression of several genes that promote cell migration and cancer progression, including ␤-catenin (Playford et al., 2000), the cadherin complex protein ZO-1 (Mauro et al., 2001), the angiogenic factor vascular endothelial growth factor (Miele et al., 2000), the metalloprotease MT1 MMP , and heparin-binding EGF-like growth factor (Mulligan et al., 2002 refractory to cellular transformation by several oncogenes (Sell et al., 1994), ...

Osteopontin Induces Ubiquitin-Dependent Degradation of STAT1 in RAW264.7 Murine Macrophages

“…For a specific substrate, E3 ligase is the only member of the E1, E2, and E3 sequence that undergoes regulation (30,31). SLIM contains a PDZ domain and a LIM domain and interacts in the nucleus with tyrosine phosphorylated STAT molecules (32). The LIM domain forms a zinc-finger structure related to the RING finger and PHD structures; similar proteins have been shown to possess E3 ligase activity (32).…”

“…SLIM contains a PDZ domain and a LIM domain and interacts in the nucleus with tyrosine phosphorylated STAT molecules (32). The LIM domain forms a zinc-finger structure related to the RING finger and PHD structures; similar proteins have been shown to possess E3 ligase activity (32). SLIM inhibits gene expression mediated by STAT4 or STAT1 by promoting ubiquitination and degradation of STAT4 and STAT1.…”

“…The cDNA encoding mouse SLIM is 1509 bp (GenBank accession no. BC024556) for mouse with an open reading frame of 349 aa (10,32). It is expressed as a 38-kDa nuclear protein.…”

PDZ Protein Interactions Underlying NMDA Receptor-Mediated Excitotoxicity and Neuroprotection by PSD-95 Inhibitors

“…In addition, LMO7, Mystique, RIL, and the LIM kinases have all been linked to carcinogenesis and metastasis (Te Velthuis et al, 2007). LIM Mystique is an IGF-IRregulated adapter protein located at the actin cytoskeleton that is necessary for the migratory capacity of epithelial cells (Loughran et al, 2005). In the nervous system, a role for RIL has been identified as directing the transport of GluR-A-containing AMPA receptors to and/or within dendritic spines, in an ␣-actinin/ actin-dependent manner, thus promoting the synaptic accumulation of the receptors (Schulz et al, 2004).…”

Heme-binding Protein HRG-1 Is Induced by Insulin-like Growth Factor I and Associates with the Vacuolar H+-ATPase to Control Endosomal pH and Receptor Trafficking

“…In an effort to identify IGF-I-regulated proteins that are important for cancer progression, we isolated a series of genes that are differentially expressed in nontransformed cells (R Ϫ , derived from the IGF-IR knock-out mouse) and highly transformed cells (R ϩ and R Ϫ cells that overexpress the IGF-IR) (17)(18)(19). Among these was a gene encoding an endosomal protein that we found to associate with the endosomal V-ATPase and to regulate V-ATPase activity in endosomes.…”