Son of sevenless
DEVELOPMENTAL BIOLOGY

Effects of Mutation or Deletion

Calmodulin and Son of sevenless dependent signaling pathways regulate midline crossing of axons in the Drosophila CNS

The establishment of axon trajectories is ultimately determined by the integration of intracellular signaling pathways. Here, a genetic approach in Drosophila has demonstrated that both Calmodulin and Son of sevenless signaling pathways are used to regulate which axons cross the midline. A loss in either signaling pathway leads to abnormal projection of axons across the midline and these increase with roundabout or slit mutations. When both Calmodulin and Son of sevenless are disrupted, the midline crossing of axons mimics that seen in roundabout mutants, although Roundabout remains expressed on crossing axons. Calmodulin and Son of sevenless also regulate axon crossing in a commissureless mutant. These data suggest that Calmodulin and Son of sevenless signaling pathways function to interpret midline repulsive cues that prevent axons crossing the midline (Fritz, 2000).

A novel CaM inhibitor, called kinesin-antagonist (KA), has been expressed using the neurogenic enhancer element of the fushi tarazu gene (ftzng) in a subset of CNS neurons that normally do not cross the midline. KA expression decreases endogenous CaM activation of target proteins in the growth cone and this leads to specific axon guidance defects including stalls at selected choice points, failure to fasciculate properly and abnormal crossing of the midline. robo and slit mutations and KA interact synergistically to increase the number of axon bundles abnormally crossing the midline. KA also induces axon bundles to cross the midline in the absence of Comm protein. Sos-dependent crossovers are enhanced by KA or by slit mutation. KA and Sos also interact to increase the number of axon bundles crossing in a comm mutant. Thus, the data demonstrate that both CaM and Sos signaling pathways are required to prevent certain axons crossing the midline (Fritz, 2000).

Whether CaM and Sos-mediated signaling is working directly downstream of Robo or in closely associated, but parallel signaling pathways to prevent axons from crossing is difficult to ascertain from this genetic data alone. If these signaling pathways lie downstream of Robo, the data suggest that both CaM and Sos are activated upon Slit binding to Robo, and result in growth cone repulsion. Interestingly, increased levels of calcium have been implicated in growth cone retraction and growth cone collapse, two ways in which a growth cone may respond to a repulsive agent. In addition, retrograde actin flow, which leads to filopodial retraction, is stimulated by CaM activation of myosin light chain kinase. Two other CaM target proteins, cAMP adenylyl cyclase and phosphodiesterase, regulate cAMP cellular concentrations thus altering neuronal response to Netrin 1 and other guidance cues. Activation of a Sos signaling pathway can affect cytoskeletal dynamics by activating various GTPases known to regulate growth cone behavior and axon guidance. Moreover, the cytoplasmic tail of Robo, known to be essential for signaling function, has a tyrosine residue that could recruit Sos via Drk or dreadlocks (dock), another SH2-SH3 adapter protein that affects axon guidance. Alternatively, Robo may bind Enabled, a known substrate for Abelson tyrosine kinase (Abl), which has been implicated in commissure formation. If Sos binds to phosphotyrosine residues on Ena (also via an adapter protein) it could be indirectly recruited to Robo (Fritz, 2000 and references therein).

Another possibility is that a disruption in both the CaM and Sos signaling pathways indirectly causes abnormal crossovers. CaM has been identified as a player downstream of several guidance molecules. Indeed, the gaps in the longitudinal connectives observed with increasing copies of KA in a comm mutant or in KA robo mutants, which are not seen in robo mutants alone, suggest CaM may function downstream of other guidance cue receptors to allow extension through the connective. Once these signals are attenuated by expression of KA, axons may inadvertently cross the midline. However, if CaM only functions in cell adhesive mechanisms within the connectives, it is difficult to explain why axons cross the midline in comm mutants when no other axons cross and the presence of Slit is still being read by Robo (Fritz, 2000 and references therein).

Since CaM and Sos appear to interpret a midline repulsive cue, the existence of an additional midline repulsion system working in parallel to Robo represents an interesting possibility. In robo mutants, axons cross the midline but then move to the longitudinal connective, instead of collapsing at the midline as observed in slit mutants. It has been suggested that this occurs because the continued presence of Slit at the midline is detected by a second receptor system, and candidate genes include a second robo gene or karussel. As the data shows, heterozygous slit mutations interact very strongly with single copies of KA, Sos or KA Sos together, to force axons across the midline. The interaction between Sos and slit mutations, especially when compared to the lack of Sos and robo interaction, is particularly striking. It seems that if the activity of both repulsion systems is decreased due to the reduction of a common ligand (Slit), a disruption in CaM and/or Sos signaling dramatically increases midline crossing errors. Most of these results, including the synergistic effects of KA and Sos, robo and slit mutations, the robo-like phenotype of KA Sos mutants, and the enhancement of crossovers in comm mutants can be explained by a parallel decrease in both midline repulsive systems upon disruption of the CaM and Sos signaling pathways. Thus while the mechanisms by which CaM and Sos contribute to an axon guidance decision at the midline remain unclear, the data clearly indicate that CaM and Sos signaling pathways are critical to the transduction of repulsive information at the midline (Fritz, 2000 and references therein).

Regulation of rho family GTPases is required to prevent axons from crossing the midline

Rho family GTPases are ideal candidates to regulate aspects of cytoskeletal dynamics downstream of axon guidance receptors. To examine the in vivo role of Rho GTPases in midline guidance, dominant negative (dn) and constitutively active (ct) forms of Rho, Drac1, and Dcdc42 are expressed in the Drosophila CNS. When expressed alone, only ctDrac and ctDcdc42 cause axons in the pCC/MP2 pathway to cross the midline inappropriately. Heterozygous loss of Roundabout enhances the ctDrac phenotype and causes errors in embryos expressing dnRho or ctRho. Homozygous loss of Son-of-Sevenless (Sos) also enhances the ctDrac phenotype and causes errors in embryos expressing either dnRho or dnDrac. CtRho suppresses the midline crossing errors caused by loss of Sos. CtDrac and ctDcdc42 phenotypes are suppressed by heterozygous loss of Profilin, but strongly enhanced by coexpression of constitutively active myosin light chain kinase (ctMLCK), which increases myosin II activity. Expression of ctMLCK also causes errors in embryos expressing either dnRho or ctRho. These data confirm that Rho family GTPases are required for regulation of actin polymerization and/or myosin activity and that this is critical for the response of growth cones to midline repulsive signals. Midline repulsion appears to require down-regulation of Drac1 and Dcdc42 and activation of Rho (Fritz, 2002).

Thus, when expressed alone, only ctDrac and ctDcdc42 cause midline crossing errors. However, the mutant GTPases interact genetically with mutations in robo, Sos, and chic and with overexpression of ctMLCK. The interactions are surprisingly specific. Midline crossing errors caused by expression of ctDrac or ctDcdc42 are suppressed by heterozygous loss of Profilin and enhanced by expression of ctMLCK. These results indicate that Drac1 and Dcdc42 encourage axons to cross the midline by regulating actin polymerization and/or myosin activity. CtRho and dnRho interact strongly with expression of ctMLCK or heterozygous loss of Robo, which suggests that regulation of myosin activity by Rho is crucial for midline repulsion. This work demonstrates that Rho, Drac1, and Dcdc42 are involved in dictating which axon may cross the midline, presumably by aiding in the transduction of attractive and/or repulsive cues operating at the midline. By using mutations in signaling molecules known to prevent pCC/MP2 axons from crossing the midline, this analysis concentrates on how Rho, Drac1, and Dcdc42 may regulate cytoskeletal dynamics in response to midline repulsive cues (Fritz, 2002).

Expression of dnRho may specifically interfere with retraction of filopodia in response to repulsive cues, leading to increased midline crossing errors. A global increase in myosin activity caused by expression of either ctRho or ctMLCK, or even a Rho GEF, may cause axon guidance errors by increasing the forward movement of the growth cone. Midline attractive activity (e.g., Netrins) probably also influences how much myosin activity is available to move a growth cone over the midline. The literature and these experiments are most consistent with a model in which Rho is activated by repulsive guidance signals. Activation of ephrinA5 receptors causes an increase in Rho activity resulting in a growth cone collapse. Plexin B, the receptor for repulsive semaphorins, binds to and seems to activate Rho. Activation of Robo by Slit recruits srGAP1, which appears to prevent it from binding to and inactivating Rho. The genetic interactions seen between Sose49 mutations and expression of ctRho or dnRho are consistent with Sos acting as a GEF for Rho in pCC/MP2 neurons. DnRho strongly enhances the midline crossing errors caused by loss of Sos, while ctRho almost completely suppresses them. Since Sos-dependent signaling pathways are required for response to midline repulsive cues, this is further evidence that Rho is activated downstream of repulsive guidance signals, although a role downstream of selected attractants cannot be ruled out (Fritz, 2002).

Clearly, regulation of Rho family GTPase activity is necessary to prevent axons from crossing the midline inappropriately. Midline repulsive signaling involves regulation of all three GTPases; Drac1 and Dcdc42 are likely downregulated, while Rho seems to be activated downstream of repulsive signals. The Rho family GTPases influence actin polymerization and/or myosin force generation to regulate the processes of growth cone motility that are required for proper response to axon guidance signals (Fritz, 2002).

New class of Sos alleles highlights the complexities of Sos function; A single amino acid substitution in the RacGEF motif

The guanine nucleotide exchange factor (GEF) Son-of-sevenless (Sos) encodes a complex multidomain protein best known for its role in activating the small GTPase RAS in response to receptor tyrosine kinase (RTK) stimulation. Much less well understood is SOS's role in modulating RAC activity via a separate GEF domain. In the course of a genetic modifier screen designed to investigate the complexities of RTK/RAS signal transduction, a complementation group of 11 alleles was isolated and mapped to the Sos locus. Molecular characterization of these alleles indicates that they specifically affect individual domains of the protein. One of these alleles, SosM98, which contains a single amino acid substitution in the RacGEF motif, functions as a dominant negative in vivo to downregulate RTK signaling. These alleles provide new tools for future investigations of SOS-mediated activation of both RAS and RAC and how these dual roles are coordinated and coregulated during development (Silver, 2004).

DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris

Nervous system injury or disease leads to activation of glia, which govern postinjury responses in the nervous system. Axonal injury in Drosophila results in transcriptional upregulation of the glial engulfment receptor Draper; there is extension of glial membranes to the injury site (termed activation), and then axonal debris is internalized and degraded. Loss of the small GTPase Rac1 from glia completely suppresses glial responses to injury, but upstream activators remain poorly defined. Loss of the Rac guanine nucleotide exchange factor (GEF) Crk/myoblast city (Mbc)/dCed-12 has no effect on glial activation, but blocks internalization and degradation of debris. This study shows that the signaling molecules Downstream of receptor kinase (DRK) and Daughter of sevenless (DOS) (mammalian homologs, Grb2 and Gab2, respectively) and the GEF Son of sevenless (SOS) (mammalian homolog, mSOS) are required for efficient activation of glia after axotomy and internalization/degradation of axonal debris. At the earliest steps of glial activation, DRK/DOS/SOS function in a partially redundant manner with Crk/Mbc/dCed-12, with blockade of both complexes strongly suppressing all glial responses, similar to loss of Rac1. This work identifies DRK/DOS/SOS as the upstream Rac GEF complex required for glial responses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris (Lu, 2014).


REFERENCES

Search PubMed for articles about Drosophila

Adams, A., et al. (2000). Intersectin, an adaptor protein involved in clathrin-mediated endocytosis, activates mitogenic signaling pathways. J. Biol Chem. 275: 27414-27420. Medline abstract: 10851244

Bonfini, L., Karlovich. C. A., Dasgupta, C. and Banerjee, U. (1992). The Son of sevenless gene product: A putative activator of Ras. Science 255: 603-606. Medline abstract: 1736363

Boriack-Sjodin, P. A., et al. (1998). The structural basis of the activation of Ras by Sos. Nature 394: 337-343. Medline abstract: 11333268

Bowtell, D., Fu, P, Simon, M, and Senior, P. (1992). Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc. Natl. Acad. Sci. 89(14): 6511-5. Medline abstract: 1631150

Brambilla, R., et al. (1997). A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390(6657): 281-286. Medline abstract: 9384379

Buday, L and Downward, J. (1993). Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73: 611-620. Medline abstract: 8490966

Byrne, J. L., Paterson, H. F. and Marshall, C. J. (1996). p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand-dependent signal involving the Sos N-terminus. Oncogene 13 (10): 2055-2065. Medline abstract: 8950972

Chang, C., Hopper, N. A. and Sternberg, P. W. (2000). Caenorhabditis elegans SOS-1 is necessary for multiple RAS-mediated developmental signals. EMBO J. 19: 3283-3294. Medline abstract: 10880441

Corbalan-Garcia, S., et al. (1998). Regulation of Sos activity by intramolecular interactions. Mol. Cell. Biol. 18(2): 880-886. Medline abstract: 9447984

Egan, S. E., et al. (1993). Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363 (6424): 45-51. Medline abstract: 8479536

Fan, W. T., et al. (1998). The exchange factor Ras-GRF2 activates Ras-dependent and Rac-dependent mitogen-activated protein kinase pathways. Curr. Biol. 8(16): 935-8. Medline abstract: 9707409

Fan, X., Labrador, J. P., Hing, H. and Bashaw, G. J. (2003). Slit stimulation recruits Dock and Pak to the Roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midline. Neuron 40: 113-127. Medline abstract: 14527437

Farnsworth, C. L., et al. (1995). Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature 376: 524-527. Medline abstract: 8479536

Freedman, T. S., et al. (2006). A Ras-induced conformational switch in the Ras activator Son of sevenless. Proc. Natl. Acad. Sci 103: 16692-16697. Medline abstract: 17075039

Fritz, J. L. and VanBerkum, M. F. A. (2000). Calmodulin and Son of sevenless dependent signaling pathways regulate midline crossing of axons in the Drosophila CNS. Development 127: 1991-2000. Medline abstract: 10751187

Fritz, J. L. and VanBerkum, M. F. A. (2002). Regulation of rho family GTPases is required to prevent axons from crossing the midline. Dev. Bio. 252: 46-58. Medline abstract: 12453459

Gale, N. W., Kaplan, S., Lowenstein, E. J., Schlessinger, J. and Bar-Sagi, D. (1993). Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature 363: 88-92. Medline abstract: 8386805

Guo, Z., Ahmadian, M. R. and Goody, R. S. (2005). Guanine nucleotide exchange factors operate by a simple allosteric competitive mechanism. Biochemistry 44: 15423-15429. Medline abstract: 16300389

Hall, B. E., et al. (2001). Structure-based mutagenesis reveals distinct functions for Ras switch 1 and switch 2 in Sos-catalyzed guanine nucleotide exchange. J. Biol. Chem. 276: 27629-27637. Medline abstract: 11333268

Hing, H., et al. (1999). Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila. Cell 97: 853-863. Medline abstract: 10399914

Hu, H., et al. (2005). Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion. Proc. Natl. Acad. Sci. 102: 4613-4618. Medline abstract: 15755809

Hu, Q., Milfay, D. and William, L. T. (1995). Binding of NCK to SOS and activation of ras-dependent gene expression, Mol. Cell. Biol. 15: 1169-1174. Medline abstract: 7862111

Innocenti, M., et al. (2002). Mechanisms through which Sos-1 coordinates the activation of Ras and Rac. J. Cell Biol. 156: 125-136. Medline abstract: 11777939

Innocenti, M., et al. (2003). Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1. J. Cell Biol. 160: 17-23. Medline abstract: 12515821

Iversen, L., Tu, H. L., Lin, W. C., Christensen, S. M., Abel, S. M., Iwig, J., Wu, H. J., Gureasko, J., Rhodes, C., Petit, R. S., Hansen, S. D., Thill, P., Yu, C. H., Stamou, D., Chakraborty, A. K., Kuriyan, J. and Groves, J. T. (2014). Molecular kinetics. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics. Science 345: 50-54. PubMed ID: 24994643

Karlovich, C. A., et al. (1995). In vivo functional analysis of the Ras exchange factor Son of sevenless. Science 268 (5210): 576-579. Medline abstract: 7725106

Kim, J. H., Shirouzu, M., Kataoka, T., Bowtell, D. and Yokoyama, S. (1998). Activation of Ras and its downstream extracellular signal-regulated protein kinases by the CDC25 homology domain of mouse Son-of-sevenless 1 (mSos1). Oncogene 16(20): 2597-607. Medline abstract: 9632136

Kim, S. Y., Kim, J. Y., Malik, S., Son, W., Kwon, K-S., et al. (2012). Negative Regulation of EGFR/MAPK Pathway by Pumilio in Drosophila melanogaster. PLoS ONE 7(4): e34016. PubMed ID: 22514614

Lenzen, C., Cool, R. H., Prinz, H., Kuhlmann, J. and Wittinghofer, A. (1998). Kinetic analysis by fluorescence of the interaction between Ras and the catalytic domain of the guanine nucleotide exchange factor Cdc25Mm. Biochemistry 37: 7420-7430. Medline abstract: 9585556

Li, N., et al. (1993). Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363: 85-88. Medline abstract: 8479541

Lu, T. Y., Doherty, J. and Freeman, M. R. (2014). DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris. Proc Natl Acad Sci U S A. PubMed ID: 25099352

Lundström, A., et al. (2004). Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons. Genes Dev. 18: 2161-2171. Medline abstract: 15342493

Margarit, S. M., et al. (2003). Structural evidence for feedback activation by Ras-GTP of the Ras-specific nucleotide exchange factor SOS. Cell 112: 685-695. Medline abstract: 12628188

Matsuura, R., Tanaka, H. and Go, M. J. (2004). Distinct functions of Rac1 and Cdc42 during axon guidance and growth cone morphogenesis in Drosophila, Eur. J. Neurosci. 19: 21-31. Medline abstract: 14750960

Mattingly, R. R. and Macara, I. G. (1996). Phosphorylation-dependent activation of the Ras-GRF/CDC25Mm exchange factor by muscarinic receptors and G-protein beta gamma subunits. Nature 382(6588): 268-72. Medline abstract: 8717044

McCollam, L., et al. (1995). Functional roles for the pleckstrin and Dbl homology regions in the Ras exchange factor Son-of-sevenless. J. Biol. Chem. 270 (27): 15954-15957. Medline abstract: 7608150

Medema, R. H., et al. (1993). Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol. Cell. Biol. 13: 155-162. Medline abstract: 8417322

Nimnual A. S., Yatsula, B.A. and Bar-Sagi, D. (1998). Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos. Science 279; 560-563. Medline abstract: 9438849

Nimnual, A. and Bar-Sagi, D. (2002). The two hats of SOS. Sci. STKE PE36. Medline abstract: 12177507

O'Bryan, J. P., Mohney, R. P. and Oldham, C. E. (2001). Mitogenesis and endocytosis: What's at the INTERSECTIoN? Oncogene 20(44): 6300-8. Medline abstract: 11607832

Oh-hora, M., Johmura, S., Hashimoto, A., Hikida, M. and Kurosaki, T. (2003). Requirement for Ras guanine nucleotide releasing protein 3 in coupling phospholipase C-gamma2 to Ras in B cell receptor signaling. J. Exp. Med. 198(12): 1841-51. Medline abstract: 14676298

Okada, S. and Pessin, J. E. (1996). Interactions between Src homology (SH) 2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor. J. Biol. Chem. 271: 25533-25538. Medline abstract: 8810325

Olivier, J. P., et al. (1993). A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell 73: 179-191. Medline abstract: 8462098

Porfiri, E. and McCormick, F. (1996). Regulation of epidermal growth factor receptor signaling by phosphorylation of the ras exchange factor hSOS1. J. Biol. Chem. 271: 5871-5877. Medline abstract: 8621459

Raabe, T., et al. (1995). Biochemical and genetic analysis of the Drk SH2/SH3 adaptor protein of Drosophila. EMBO J. 14: 2509-2518. Medline abstract: 7781603

Rong, R., Ahn, J. Y., Chen, P., Suh, P. G. and Ye, K. (2004) Phospholipase activity of phospholipase C-gamma1 is required for nerve growth factor-regulated MAP kinase signaling cascade in PC12 cells. J. Biol. Chem. 278(52): 52497-503. Medline abstract: 14570902

Rozakis-Adcock, M., et al. (1993). The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature 363 (6424): 83-85. Medline abstract: 8479540

Scita, B., et al. (1999). EPS8 and E3B1 transduce signals from Ras to Rac. Nature 401: 290-293. Medline abstract: 10499589

Scita, G., et al. (2000). Signaling from Ras to Rac and beyond: Not just a matter of GEFs, EMBO J. 19: 2393-2398. Medline abstract: 10835338

Silver, S. J., Chen, F., Doyon, L., Zink, A. W. and Rebay, I. (2004). New class of Son-of-sevenless (Sos) alleles highlights the complexities of Sos function. Genesis 39: 263-272. Medline abstract: 15286999

Simon, M. A., et al. (1991). Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67: 701-716. Medline abstract: 1934068

Simon, M. A., Dodson, G. S. and Rubin, G. M. (1993). An SH3-SH2-SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro. Cell 73: 169-177. Medline abstract: 8462097

Sini, P, et al. (2004). Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation. Nat. Cell Biol. 6: 268-274. Medline abstract: 15039778

Sondermann, H., et al. (2004). Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell 119(3): 393-405. Medline abstract: 15507210

Tian, X., et al. (2004). Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB. EMBO J. 23(7): 1567-75. Medline abstract: 15029245

Tong, X.-K., et al. (2000a). The endocytic protein intersectin is a major binding partner for the Ras exchange factor mSos1 in rat brain. EMBO J. 19: 1263-1271. Medline abstract: 10716926

Tong, X. K., et al. (2000b). Intersectin can regulate the Ras/MAP kinase pathway independent of its role in endocytosis. J. Biol. Chem. 275(38): 29894-9. Medline abstract: 10896662

Wei, W., Schreiber, S. S., Baudry, M., Tocco, G. and Broek, D. (1993). Localization of the cellular expression pattern of cdc25NEF and ras in the juvenile rat brain. Brain Res. Mol. Brain Res. 19(4): 339-44. Medline abstract: 8231737

Wong, K., et al. (2001). Signal transduction in neuronal migration: Roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway. Cell 107: 209-221. Medline abstract: 11672528

Yang, L. and Bashaw, G. J. (2006). Son of sevenless directly links the Robo receptor to rac activation to control axon repulsion at the midline. Neuron 52(4): 595-607. Medline abstract: 17114045

Ye, B., et al. (2000). GRASP-1: A neuronal RasGEF associated with the AMPA receptor/GRIP complex. Neuron 26: 603-617. Medline abstract: 10896157


Son of sevenless: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 23 August 2014

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