Human Tumorous Imaginal Disc 1 (TID1) Associates with Trk Receptor Tyrosine Kinases and Regulates Neurite Outgrowth in nnr5-TrkA Cells

Abstract

The human tumorous imaginal disc 1 (TID1) proteins including TID1 L and TID1 S , members of the DnaJ domain protein family, are involved in multiple intracellular signaling pathways such as apoptosis induction, cell proliferation, and survival. Here we report that TID1 associates with the Trk receptor tyrosine kinases and regulates nerve growth factor (NGF)-induced neurite outgrowth in PC12-derived nnr5 cells. Binding assays and transfection studies showed that the carboxyl-terminal end of TID1 (residues 224 -429) bound to Trk at the activation loop (Tyr(P) 683 -Tyr 684 (P) 684 in rat TrkA) and that TID1 was tyrosine phosphorylated by Trk both in yeast and in transfected cells. Moreover endogenous TID1 was also tyrosine phosphorylated by and co-immunoprecipitated with Trk in neurotrophinstimulated primary rat hippocampal neurons. Overexpression studies showed that both TID1 L and TID1 S significantly facilitated NGF-induced neurite outgrowth in TrkA-expressing nnr5 cells possibly through a mechanism involving increased activation of mitogen-activated protein kinase. Consistently knockdown of endogenous TID1, mediated with specific short hairpin RNA, significantly reduced NGF-induced neurite growth in nnr5-TrkA cells. These data provide the first evidence that TID1 is a novel intracellular adaptor that interacts with the Trk receptor tyrosine kinases in an activity-dependent manner to facilitate Trk-dependent intracellular signaling.

Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor

“…Its isolation as a molecular ligand of oncogenes, tumor suppressors and other cancer-related molecules supports its causal involvement in tumor onset via different modes (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Our recent identification of Tid50/Tid48 as APC partner (22) extends the list of its tumor-related physiological ligands and, furthermore, provides additional proof for its action at different levels of cancer-related signaling networks.…”

“…Total cellular RNA was extracted from frozen tissue specimens using RNeasy Mini kit (Qiagen), primed with a dT 18 oligonucleotide and reverse-transcribed with Superscript II (Invitrogen) in accordance with the manufacturer's instructions. The integrity of the obtained cDNA was tested by amplification of p53 transcripts in a 30-cycle PCR at 67˚C using the primers 5'-CGT GAG CGC TTC GAG ATG TCC G-3' (sense) and 5'-CCT AAC CAG CTG CCC AAC TGT AG-3' (antisense).…”

“…The involvement of dtid in the Hh-mediated signaling is mediated by binding of the cytosolic Tid47 protein to the Hh-bound Patched (Ptc) receptor (12). Htid-1, the human counterpart of dtid, was isolated by yeast two-hybrid screening as a molecular partner of diverse tumor-related proteins such as the E7 oncoprotein (13), the human interferon-γ receptor subunit R2 (IFN-γR2) (14), the oncogenic viral Tax protein encoded by the human T cell leukemia virus type 1 (HTLV-1) (15), the repressor of IκB kinase ß subunit (16), the ErbB-2 receptor tyrosine kinase (17), the Trk receptor kinases (18) and the von Hippel-Lindau tumor suppressor (19). The murine homolog, mtid-1, was identified in a yeast two-hybrid screen as ligand of the Ras GTPase activating protein (GAP) (20).…”

Prolonged Treatment of Primary Hepatocytes with Oleate Induces Insulin Resistance through p38 Mitogen-activated Protein Kinase

“…Immunoprecipitation and Western Blotting-Cells were lysed in Nonidet P-40 lysis buffer (1% Nonidet P-40, 150 mM NaCl, 10% glycerol, 2 mM EDTA, 20 mM Tris (pH 8.0), 1 mM dithiothreitol, 1 mM sodium orthovanadate, 1 mM phenylmethylsulfonyl fluoride, 2 g/ml leupeptin, and 10 g/ml aprotinin (32). Cell lysates (15 g per lane) were resolved in 10% Tris-glycine gels (Invitrogen) and transferred to nitrocellulose membranes (Bio-Rad).…”

Interaction of Mint2 with TrkA Is Involved in Regulation of Nerve Growth Factor-induced Neurite Outgrowth

“…The resulting phosphotyrosines become docking sites for adaptor proteins involved in signal transduction pathways that lead to the activation of Ras, Rac, phosphatidylinositol 3-kinase, phospholipase C␥, and other effectors (2,6). Many of these TrkA-interacting adaptor proteins have been identified and include, Grb2, APS, SH2B, fibroblast growth factor receptor substrate 2 (FRS-2), Shc, and human tumor imaginal disc 1 (TID1) (7)(8)(9)(10). The identification of these binding partners has contributed greatly to our understanding of the mechanisms underlying the functional diversity of NGF-TrkA signaling.…”