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Proc Natl Acad Sci U S A. May 28, 1996; 93(11): 5466–5471.
PMCID: PMC39269

The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains.

Abstract

rho-like GTP binding proteins play an essential role in regulating cell growth and actin polymerization. These molecular switches are positively regulated by guanine nucleotide exchange factors (GEFs) that promote the exchange of GDP for GTP. Using the interaction-trap assay to identify candidate proteins that bind the cytoplasmic region of the LAR transmembrane protein tyrosine phosphatase (PT-Pase), we isolated a cDNA encoding a 2861-amino acid protein termed Trio that contains three enzyme domains: two functional GEF domains and a protein serine/threonine kinase (PSK) domain. One of the Trio GEF domains (Trio GEF-D1) has rac-specific GEF activity, while the other Trio GEF domain (Trio GEF-D2) has rho-specific activity. The C-terminal PSK domain is adjacent to an Ig-like domain and is most similar to calcium/calmodulin-dependent kinases, such as smooth muscle myosin light chain kinase which similarly contains associated Ig-like domains. Near the N terminus, Trio has four spectrin-like repeats that may play a role in intracellular targeting. Northern blot analysis indicates that Trio has a broad tissue distribution. Trio appears to be phosphorylated only on serine residues, suggesting that Trio is not a LAR substrate, but rather that it forms a complex with LAR. As the LAR PTPase localizes to the ends of focal adhesions, we propose that LAR and the Trio GEF/PSK may orchestrate cell-matrix and cytoskeletal rearrangements necessary for cell migration.

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  • Hall A. Small GTP-binding proteins and the regulation of the actin cytoskeleton. Annu Rev Cell Biol. 1994;10:31–54. [PubMed]
  • Boguski MS, McCormick F. Proteins regulating Ras and its relatives. Nature. 1993 Dec 16;366(6456):643–654. [PubMed]
  • Vojtek AB, Cooper JA. Rho family members: activators of MAP kinase cascades. Cell. 1995 Aug 25;82(4):527–529. [PubMed]
  • Takai Y, Sasaki T, Tanaka K, Nakanishi H. Rho as a regulator of the cytoskeleton. Trends Biochem Sci. 1995 Jun;20(6):227–231. [PubMed]
  • Nobes CD, Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell. 1995 Apr 7;81(1):53–62. [PubMed]
  • Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992 Aug 7;70(3):389–399. [PubMed]
  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995 Jun 30;81(7):1137–1146. [PubMed]
  • Minden A, Lin A, Claret FX, Abo A, Karin M. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell. 1995 Jun 30;81(7):1147–1157. [PubMed]
  • Olson MF, Ashworth A, Hall A. An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science. 1995 Sep 1;269(5228):1270–1272. [PubMed]
  • Qiu RG, Chen J, Kirn D, McCormick F, Symons M. An essential role for Rac in Ras transformation. Nature. 1995 Mar 30;374(6521):457–459. [PubMed]
  • Khosravi-Far R, Solski PA, Clark GJ, Kinch MS, Der CJ. Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol. 1995 Nov;15(11):6443–6453. [PMC free article] [PubMed]
  • Hill CS, Wynne J, Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell. 1995 Jun 30;81(7):1159–1170. [PubMed]
  • Hart MJ, Eva A, Evans T, Aaronson SA, Cerione RA. Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product. Nature. 1991 Nov 28;354(6351):311–314. [PubMed]
  • Hart MJ, Eva A, Zangrilli D, Aaronson SA, Evans T, Cerione RA, Zheng Y. Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product. J Biol Chem. 1994 Jan 7;269(1):62–65. [PubMed]
  • Horii Y, Beeler JF, Sakaguchi K, Tachibana M, Miki T. A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways. EMBO J. 1994 Oct 17;13(20):4776–4786. [PMC free article] [PubMed]
  • Zheng Y, Olson MF, Hall A, Cerione RA, Toksoz D. Direct involvement of the small GTP-binding protein Rho in lbc oncogene function. J Biol Chem. 1995 Apr 21;270(16):9031–9034. [PubMed]
  • Michiels F, Habets GG, Stam JC, van der Kammen RA, Collard JG. A role for Rac in Tiam1-induced membrane ruffling and invasion. Nature. 1995 May 25;375(6529):338–340. [PubMed]
  • Zheng Y, Cerione R, Bender A. Control of the yeast bud-site assembly GTPase Cdc42. Catalysis of guanine nucleotide exchange by Cdc24 and stimulation of GTPase activity by Bem3. J Biol Chem. 1994 Jan 28;269(4):2369–2372. [PubMed]
  • Streuli M, Krueger NX, Ariniello PD, Tang M, Munro JM, Blattler WA, Adler DA, Disteche CM, Saito H. Expression of the receptor-linked protein tyrosine phosphatase LAR: proteolytic cleavage and shedding of the CAM-like extracellular region. EMBO J. 1992 Mar;11(3):897–907. [PMC free article] [PubMed]
  • Yu Q, Lenardo T, Weinberg RA. The N-terminal and C-terminal domains of a receptor tyrosine phosphatase are associated by non-covalent linkage. Oncogene. 1992 Jun;7(6):1051–1057. [PubMed]
  • Fischer EH, Charbonneau H, Tonks NK. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science. 1991 Jul 26;253(5018):401–406. [PubMed]
  • Mourey RJ, Dixon JE. Protein tyrosine phosphatases: characterization of extracellular and intracellular domains. Curr Opin Genet Dev. 1994 Feb;4(1):31–39. [PubMed]
  • Serra-Pagès C, Kedersha NL, Fazikas L, Medley Q, Debant A, Streuli M. The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J. 1995 Jun 15;14(12):2827–2838. [PMC free article] [PubMed]
  • Gyuris J, Golemis E, Chertkov H, Brent R. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell. 1993 Nov 19;75(4):791–803. [PubMed]
  • Streuli M, Krueger NX, Hall LR, Schlossman SF, Saito H. A new member of the immunoglobulin superfamily that has a cytoplasmic region homologous to the leukocyte common antigen. J Exp Med. 1988 Nov 1;168(5):1523–1530. [PMC free article] [PubMed]
  • Streuli M, Hall LR, Saga Y, Schlossman SF, Saito H. Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens. J Exp Med. 1987 Nov 1;166(5):1548–1566. [PMC free article] [PubMed]
  • Boyle WJ, van der Geer P, Hunter T. Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol. 1991;201:110–149. [PubMed]
  • Malcolm KC, Ross AH, Qiu RG, Symons M, Exton JH. Activation of rat liver phospholipase D by the small GTP-binding protein RhoA. J Biol Chem. 1994 Oct 21;269(42):25951–25954. [PubMed]
  • Albright CF, Giddings BW, Liu J, Vito M, Weinberg RA. Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. EMBO J. 1993 Jan;12(1):339–347. [PMC free article] [PubMed]
  • Ron D, Tronick SR, Aaronson SA, Eva A. Molecular cloning and characterization of the human dbl proto-oncogene: evidence that its overexpression is sufficient to transform NIH/3T3 cells. EMBO J. 1988 Aug;7(8):2465–2473. [PMC free article] [PubMed]
  • Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A. Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 1995 Jan 1;9(1):15–30. [PubMed]
  • Tan JL, Spudich JA. Characterization and bacterial expression of the Dictyostelium myosin light chain kinase cDNA. Identification of an autoinhibitory domain. J Biol Chem. 1991 Aug 25;266(24):16044–16049. [PubMed]
  • Hanks SK, Quinn AM. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 1991;200:38–62. [PubMed]
  • Whitehead I, Kirk H, Kay R. Retroviral transduction and oncogenic selection of a cDNA encoding Dbs, a homolog of the Dbl guanine nucleotide exchange factor. Oncogene. 1995 Feb 16;10(4):713–721. [PubMed]
  • Wasenius VM, Saraste M, Salvén P, Erämaa M, Holm L, Lehto VP. Primary structure of the brain alpha-spectrin. J Cell Biol. 1989 Jan;108(1):79–93. [PMC free article] [PubMed]
  • Musacchio A, Gibson T, Rice P, Thompson J, Saraste M. The PH domain: a common piece in the structural patchwork of signalling proteins. Trends Biochem Sci. 1993 Sep;18(9):343–348. [PubMed]
  • Olson NJ, Pearson RB, Needleman DS, Hurwitz MY, Kemp BE, Means AR. Regulatory and structural motifs of chicken gizzard myosin light chain kinase. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2284–2288. [PMC free article] [PubMed]
  • Whitehead I, Kirk H, Tognon C, Trigo-Gonzalez G, Kay R. Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C. J Biol Chem. 1995 Aug 4;270(31):18388–18395. [PubMed]
  • Pitcher JA, Touhara K, Payne ES, Lefkowitz RJ. Pleckstrin homology domain-mediated membrane association and activation of the beta-adrenergic receptor kinase requires coordinate interaction with G beta gamma subunits and lipid. J Biol Chem. 1995 May 19;270(20):11707–11710. [PubMed]
  • Dhermy D. The spectrin super-family. Biol Cell. 1991;71(3):249–254. [PubMed]
  • Benian GM, Kiff JE, Neckelmann N, Moerman DG, Waterston RH. Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans. Nature. 1989 Nov 2;342(6245):45–50. [PubMed]
  • Ridley AJ, Hall A. Signal transduction pathways regulating Rho-mediated stress fibre formation: requirement for a tyrosine kinase. EMBO J. 1994 Jun 1;13(11):2600–2610. [PMC free article] [PubMed]

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