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EMBO J. Jan 2, 1997; 16(1): 121–132.
PMCID: PMC1169619

Mouse disabled (mDab1): a Src binding protein implicated in neuronal development.


Here, we identify a mouse homolog of the Drosophila Disabled (Dab) protein, mDab1, and show it is an adaptor molecule functioning in neural development. We find that mDab1 is expressed in certain neuronal and hematopoietic cell lines, and is localized to the growing nerves of embryonic mice. During mouse embryogenesis, mDab1 is tyrosine phosphorylated when the nervous system is undergoing dramatic expansion. However, when nerve tracts are established, mDab1 lacks detectable phosphotyrosine. Tyrosine-phosphorylated mDab1 associates with the SH2 domains of Src, Fyn and Abl. An interaction between mDab1 and Src is observed when P19 embryonal carcinoma (EC) cells undergo differentiation into neuronal cell types. mDab1 can also form complexes with cellular phosphotyrosyl proteins through a domain that is related to the phosphotyrosine binding (PTB) domains of the Shc family of adaptor proteins. The mDab1 PTB domain binds to phosphotyrosine-containing proteins of 200, 120 and 40 kDa from extracts of embryonic mouse heads. The properties of mDab1 and genetic analysis of Dab in Drosophila suggest that these molecules function in key signal transduction pathways involved in the formation of neural networks.

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Selected References

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  • Afar DE, Goga A, McLaughlin J, Witte ON, Sawyers CL. Differential complementation of Bcr-Abl point mutants with c-Myc. Science. 1994 Apr 15;264(5157):424–426. [PubMed]
  • Alonso G, Koegl M, Mazurenko N, Courtneidge SA. Sequence requirements for binding of Src family tyrosine kinases to activated growth factor receptors. J Biol Chem. 1995 Apr 28;270(17):9840–9848. [PubMed]
  • Henkemeyer M, West SR, Gertler FB, Hoffmann FM. A novel tyrosine kinase-independent function of Drosophila abl correlates with proper subcellular localization. Cell. 1990 Nov 30;63(5):949–960. [PubMed]
  • Hill KK, Bedian V, Juang JL, Hoffmann FM. Genetic interactions between the Drosophila Abelson (Abl) tyrosine kinase and failed axon connections (fax), a novel protein in axon bundles. Genetics. 1995 Oct;141(2):595–606. [PMC free article] [PubMed]
  • Beggs HE, Soriano P, Maness PF. NCAM-dependent neurite outgrowth is inhibited in neurons from Fyn-minus mice. J Cell Biol. 1994 Nov;127(3):825–833. [PMC free article] [PubMed]
  • Bennett RL, Hoffmann FM. Increased levels of the Drosophila Abelson tyrosine kinase in nerves and muscles: subcellular localization and mutant phenotypes imply a role in cell-cell interactions. Development. 1992 Dec;116(4):953–966. [PubMed]
  • Hollenberg SM, Sternglanz R, Cheng PF, Weintraub H. Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system. Mol Cell Biol. 1995 Jul;15(7):3813–3822. [PMC free article] [PubMed]
  • Bixby JL, Harris WA. Molecular mechanisms of axon growth and guidance. Annu Rev Cell Biol. 1991;7:117–159. [PubMed]
  • Howell BW, Cooper JA. Csk suppression of Src involves movement of Csk to sites of Src activity. Mol Cell Biol. 1994 Aug;14(8):5402–5411. [PMC free article] [PubMed]
  • Brown MT, Cooper JA. Regulation, substrates and functions of src. Biochim Biophys Acta. 1996 Jun 7;1287(2-3):121–149. [PubMed]
  • Jones-Villeneuve EM, Rudnicki MA, Harris JF, McBurney MW. Retinoic acid-induced neural differentiation of embryonal carcinoma cells. Mol Cell Biol. 1983 Dec;3(12):2271–2279. [PMC free article] [PubMed]
  • Kavanaugh WM, Williams LT. An alternative to SH2 domains for binding tyrosine-phosphorylated proteins. Science. 1994 Dec 16;266(5192):1862–1865. [PubMed]
  • Kavanaugh WM, Turck CW, Williams LT. PTB domain binding to signaling proteins through a sequence motif containing phosphotyrosine. Science. 1995 May 26;268(5214):1177–1179. [PubMed]
  • Cooper JA, Gould KL, Cartwright CA, Hunter T. Tyr527 is phosphorylated in pp60c-src: implications for regulation. Science. 1986 Mar 21;231(4744):1431–1434. [PubMed]
  • Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem. 1991 Oct 25;266(30):19867–19870. [PubMed]
  • Desai CJ, Gindhart JG, Jr, Goldstein LS, Zinn K. Receptor tyrosine phosphatases are required for motor axon guidance in the Drosophila embryo. Cell. 1996 Feb 23;84(4):599–609. [PubMed]
  • Kremer NE, D'Arcangelo G, Thomas SM, DeMarco M, Brugge JS, Halegoua S. Signal transduction by nerve growth factor and fibroblast growth factor in PC12 cells requires a sequence of src and ras actions. J Cell Biol. 1991 Nov;115(3):809–819. [PMC free article] [PubMed]
  • Druker BJ, Mamon HJ, Roberts TM. Oncogenes, growth factors, and signal transduction. N Engl J Med. 1989 Nov 16;321(20):1383–1391. [PubMed]
  • Krueger NX, Van Vactor D, Wan HI, Gelbart WM, Goodman CS, Saito H. The transmembrane tyrosine phosphatase DLAR controls motor axon guidance in Drosophila. Cell. 1996 Feb 23;84(4):611–622. [PubMed]
  • Kunkel TA, Roberts JD, Zakour RA. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 1987;154:367–382. [PubMed]
  • Eck MJ, Dhe-Paganon S, Trüb T, Nolte RT, Shoelson SE. Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell. 1996 May 31;85(5):695–705. [PubMed]
  • Feng S, Chen JK, Yu H, Simon JA, Schreiber SL. Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. Science. 1994 Nov 18;266(5188):1241–1247. [PubMed]
  • Lynch SA, Brugge JS, Levine JM. Induction of altered c-src product during neural differentiation of embryonal carcinoma cells. Science. 1986 Nov 14;234(4778):873–876. [PubMed]
  • MacAuley A, Cooper JA. The carboxy-terminal sequence of p56lck can regulate p60c-src. Mol Cell Biol. 1988 Aug;8(8):3560–3564. [PMC free article] [PubMed]
  • Maness PF, Shores CG, Ignelzi M. Localization of the normal cellular src protein to the growth cone of differentiating neurons in brain and retina. Adv Exp Med Biol. 1990;265:117–125. [PubMed]
  • Mayer BJ, Eck MJ. SH3 domains. Minding your p's and q's. Curr Biol. 1995 Apr 1;5(4):364–367. [PubMed]
  • Gertler FB, Hill KK, Clark MJ, Hoffmann FM. Dosage-sensitive modifiers of Drosophila abl tyrosine kinase function: prospero, a regulator of axonal outgrowth, and disabled, a novel tyrosine kinase substrate. Genes Dev. 1993 Mar;7(3):441–453. [PubMed]
  • Goldberg DJ, Wu DY. Inhibition of formation of filopodia after axotomy by inhibitors of protein tyrosine kinases. J Neurobiol. 1995 Aug;27(4):553–560. [PubMed]
  • Miller AD, Miller DG, Garcia JV, Lynch CM. Use of retroviral vectors for gene transfer and expression. Methods Enzymol. 1993;217:581–599. [PubMed]
  • Umemori H, Sato S, Yagi T, Aizawa S, Yamamoto T. Initial events of myelination involve Fyn tyrosine kinase signalling. Nature. 1994 Feb 10;367(6463):572–576. [PubMed]
  • Mok SC, Wong KK, Chan RK, Lau CC, Tsao SW, Knapp RC, Berkowitz RS. Molecular cloning of differentially expressed genes in human epithelial ovarian cancer. Gynecol Oncol. 1994 Feb;52(2):247–252. [PubMed]
  • Vaessin H, Grell E, Wolff E, Bier E, Jan LY, Jan YN. prospero is expressed in neuronal precursors and encodes a nuclear protein that is involved in the control of axonal outgrowth in Drosophila. Cell. 1991 Nov 29;67(5):941–953. [PubMed]
  • Mori S, Rönnstrand L, Yokote K, Engström A, Courtneidge SA, Claesson-Welsh L, Heldin CH. Identification of two juxtamembrane autophosphorylation sites in the PDGF beta-receptor; involvement in the interaction with Src family tyrosine kinases. EMBO J. 1993 Jun;12(6):2257–2264. [PMC free article] [PubMed]
  • Vaillancourt RR, Heasley LE, Zamarripa J, Storey B, Valius M, Kazlauskas A, Johnson GL. Mitogen-activated protein kinase activation is insufficient for growth factor receptor-mediated PC12 cell differentiation. Mol Cell Biol. 1995 Jul;15(7):3644–3653. [PMC free article] [PubMed]
  • Okada M, Howell BW, Broome MA, Cooper JA. Deletion of the SH3 domain of Src interferes with regulation by the phosphorylated carboxyl-terminal tyrosine. J Biol Chem. 1993 Aug 25;268(24):18070–18075. [PubMed]
  • Vojtek AB, Cooper JA. Identification and characterization of a cDNA encoding mouse CAP: a homolog of the yeast adenylyl cyclase associated protein. J Cell Sci. 1993 Jul;105(Pt 3):777–785. [PubMed]
  • Waksman G, Kominos D, Robertson SC, Pant N, Baltimore D, Birge RB, Cowburn D, Hanafusa H, Mayer BJ, Overduin M, et al. Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature. 1992 Aug 20;358(6388):646–653. [PubMed]
  • Wilson R, Ainscough R, Anderson K, Baynes C, Berks M, Bonfield J, Burton J, Connell M, Copsey T, Cooper J, et al. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature. 1994 Mar 3;368(6466):32–38. [PubMed]
  • Sabe H, Hata A, Okada M, Nakagawa H, Hanafusa H. Analysis of the binding of the Src homology 2 domain of Csk to tyrosine-phosphorylated proteins in the suppression and mitotic activation of c-Src. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3984–3988. [PMC free article] [PubMed]
  • Wu DY, Goldberg DJ. Regulated tyrosine phosphorylation at the tips of growth cone filopodia. J Cell Biol. 1993 Nov;123(3):653–664. [PMC free article] [PubMed]
  • Xu XX, Yang W, Jackowski S, Rock CO. Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. J Biol Chem. 1995 Jun 9;270(23):14184–14191. [PubMed]
  • Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol. 1994 Mar;14(3):1680–1688. [PMC free article] [PubMed]
  • Zhou MM, Ravichandran KS, Olejniczak EF, Petros AM, Meadows RP, Sattler M, Harlan JE, Wade WS, Burakoff SJ, Fesik SW. Structure and ligand recognition of the phosphotyrosine binding domain of Shc. Nature. 1995 Dec 7;378(6557):584–592. [PubMed]
  • Zhou MM, Huang B, Olejniczak ET, Meadows RP, Shuker SB, Miyazaki M, Trüb T, Shoelson SE, Fesik SW. Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain. Nat Struct Biol. 1996 Apr;3(4):388–393. [PubMed]
  • Seidel-Dugan C, Meyer BE, Thomas SM, Brugge JS. Effects of SH2 and SH3 deletions on the functional activities of wild-type and transforming variants of c-Src. Mol Cell Biol. 1992 Apr;12(4):1835–1845. [PMC free article] [PubMed]
  • Simon MA, Drees B, Kornberg T, Bishop JM. The nucleotide sequence and the tissue-specific expression of Drosophila c-src. Cell. 1985 Oct;42(3):831–840. [PubMed]
  • Snider WD. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell. 1994 Jun 3;77(5):627–638. [PubMed]
  • Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, et al. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993 Mar 12;72(5):767–778. [PubMed]
  • Songyang Z, Carraway KL, 3rd, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, et al. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature. 1995 Feb 9;373(6514):536–539. [PubMed]
  • Songyang Z, Margolis B, Chaudhuri M, Shoelson SE, Cantley LC. The phosphotyrosine interaction domain of SHC recognizes tyrosine-phosphorylated NPXY motif. J Biol Chem. 1995 Jun 23;270(25):14863–14866. [PubMed]
  • Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991 Feb 22;64(4):693–702. [PubMed]
  • Stainier DY, Gilbert W. Pioneer neurons in the mouse trigeminal sensory system. Proc Natl Acad Sci U S A. 1990 Feb;87(3):923–927. [PMC free article] [PubMed]
  • Stein PL, Lee HM, Rich S, Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. [PubMed]
  • Taylor SJ, Shalloway D. An RNA-binding protein associated with Src through its SH2 and SH3 domains in mitosis. Nature. 1994 Apr 28;368(6474):867–871. [PubMed]
  • Tessier-Lavigne M. Eph receptor tyrosine kinases, axon repulsion, and the development of topographic maps. Cell. 1995 Aug 11;82(3):345–348. [PubMed]
  • Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991 Jun 28;65(7):1153–1163. [PubMed]

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