Netrin Stimulates Tyrosine Phosphorylation of the UNC-5 Family of Netrin Receptors and Induces Shp2 Binding to the RCM Cytodomain

Caenorhabditis elegans UNC-5 and its mammalian homologues such as RCM are receptors for the secreted axon guidance cue UNC-6/netrin and are required to mediate the repulsive effects of UNC-6/netrin on growth cones. We find that C. elegans UNC-5 and mouse RCM are phosphorylated on tyrosinein vivo. C. elegans UNC-5 tyrosine phosphorylation is reduced in unc-6 null mutants, and RCM tyrosine phosphorylation is induced by netrin-1 in transfected HEK-293 cells, demonstrating that phosphorylation of UNC-5 proteins is enhanced by UNC-6/netrin stimulation in both worms and mammalian cells. An activated Src tyrosine kinase induces phosphorylation of RCM at multiple cytoplasmic tyrosine residues creating potential binding sites for cytoplasmic signaling proteins. Indeed, the NH2-terminal SH2 domain of the Shp2 tyrosine phosphatase bound specifically to a Tyr568 RCM phosphopeptide. Furthermore, Shp2 associated with RCM in a netrin-dependent manner in transfected cells, and co-immunoprecipitated with RCM from an embryonic mouse brain lysate. A Y568F mutant RCM receptor failed to bind Shp2 and was more highly phosphorylated on tyrosine than the wild type receptor. These results suggest that netrin-stimulated phosphorylation of RCM Tyr568 recruits Shp2 to the cell membrane where it can potentially modify RCM phosphorylation and function. Caenorhabditis elegans UNC-5 and its mammalian homologues such as RCM are receptors for the secreted axon guidance cue UNC-6/netrin and are required to mediate the repulsive effects of UNC-6/netrin on growth cones. We find that C. elegans UNC-5 and mouse RCM are phosphorylated on tyrosinein vivo. C. elegans UNC-5 tyrosine phosphorylation is reduced in unc-6 null mutants, and RCM tyrosine phosphorylation is induced by netrin-1 in transfected HEK-293 cells, demonstrating that phosphorylation of UNC-5 proteins is enhanced by UNC-6/netrin stimulation in both worms and mammalian cells. An activated Src tyrosine kinase induces phosphorylation of RCM at multiple cytoplasmic tyrosine residues creating potential binding sites for cytoplasmic signaling proteins. Indeed, the NH2-terminal SH2 domain of the Shp2 tyrosine phosphatase bound specifically to a Tyr568 RCM phosphopeptide. Furthermore, Shp2 associated with RCM in a netrin-dependent manner in transfected cells, and co-immunoprecipitated with RCM from an embryonic mouse brain lysate. A Y568F mutant RCM receptor failed to bind Shp2 and was more highly phosphorylated on tyrosine than the wild type receptor. These results suggest that netrin-stimulated phosphorylation of RCM Tyr568 recruits Shp2 to the cell membrane where it can potentially modify RCM phosphorylation and function. deleted in colorectal cancer, a receptor domain a receptor a Src domain phosphatase type in C. elegans C. elegans a C. elegans RCM a C. elegans and domain growth in the are to by and repulsive guidance proteins that in of the and of receptors for guidance and and for the of the are of the deleted in colorectal and UNC-5 receptors and are required for the of growth by in of in the in of that are to a in UNC-5 as of are required for the repulsive of the C. the of UNC-5 in that from an UNC-6/netrin results in to that of UNC-5 in that to to to from the in an manner C. to was to by of UNC-5 in that the of and more of in C. from the UNC-6/netrin to a than of in UNC-5 receptors mediate repulsive to UNC-6/netrin Furthermore, is required for the of receptors in of the UNC-5 the mammalian and a and type by a cytoplasmic a by a domain to a of and a domain A binding was the and domain of cytoplasmic of guidance receptors are repulsive A receptor of a and an cytoplasmic domain a repulsive to the netrin-1 in a that the cytoplasmic domain the of growth to the netrin-1 of cytoplasmic signaling to the that the of a growth to a guidance cue on the of the in is the of by the the signaling for the and UNC-5 receptors are C. of growth induced by UNC-5 as as to required for axon and an a UNC-5 and the of and are proteins required for axon guidance in and on the of UNC-5 We that UNC-5 receptors are tyrosine phosphorylated in and tyrosine phosphorylation can enhanced by phosphorylation in the domain is and to bind with the Shp2 tyrosine phosphatase in and in to cell growth and more signaling in the of cell and in the of such as the the of receptor tyrosine such as axon guidance and in the mammalian as as the of and the of that the Furthermore, the C. elegans receptor cell receptor signaling the and can in the of growth and in the of from that on the cytoplasmic of receptors activated in with receptor tyrosine can bind SH2 domain proteins and can the in SH2 proteins such as and Shp2 tyrosine phosphorylation as a in cell and axon to receptors with tyrosine kinase a of receptors with tyrosine and tyrosine phosphorylation to SH2 domain proteins and for with cytoplasmic tyrosine the activated creating binding sites for the SH2 of that a of guidance kinase as for tyrosine and by tyrosine the repulsive effects of the on of the can phosphorylated on multiple tyrosine residues by the tyrosine kinase of of the tyrosine phosphorylation sites the a receptor that of tyrosine phosphorylation is to the of a receptor is tyrosine phosphorylated and the SH2 domain of the in a that for the of receptors mediate the effects of the guidance tyrosine phosphorylated in the an and cytoplasmic signaling tyrosine kinase that phosphorylation results from an associated tyrosine of tyrosine phosphorylation in axon guidance in is by the that tyrosine are in of from cell to axon guidance and in that tyrosine and are of repulsive signaling results that of the UNC-5 of guidance receptors are for tyrosine phosphorylation in of in and in at the is the signaling activated by the receptors and is phosphorylation the that kinase We find that the netrin-1 UNC-5 and are both phosphorylated on tyrosine in C. elegans and that the tyrosine phosphorylation of UNC-5 in is on UNC-5 to multiple tyrosine phosphorylation sites and it is that the tyrosine phosphorylation of UNC-5 in an unc-6 null mutant of C. is to phosphorylation sites a on as as is the of UNC-5 on it is that for UNC-5 that its to to A for UNC-5 is a of that is required to the of C. in growth guidance to a growth receptor and is a potential for UNC-5 by its to These are to the of UNC-5 tyrosine by that with tyrosine phosphorylation a reduced to null of C. These results suggest that tyrosine phosphorylation is a of UNC-5 and the that tyrosine phosphorylation is for UNC-5 in vivo. that UNC-5 tyrosine phosphorylation is the that mammalian RCM is tyrosine phosphorylated in the embryonic mouse that UNC-5 is in HEK-293 transfected cells, RCM is phosphorylated stimulation both the and netrin-stimulated tyrosine phosphorylation is enhanced by the of an activated Src tyrosine are for the RCM tyrosine phosphorylation in HEK-293 to in by a such as an in cell RCM phosphorylation by a tyrosine kinase is activated in HEK-293 cells. of the tyrosine kinase that UNC-5 in to the that UNC-5 and RCM elegans and the mouse that phosphorylation is a UNC-5 phosphorylation tyrosine and of proteins These that a tyrosine the domain is of the potential tyrosine phosphorylation sites in of RCM Tyr568 an SH2 and Shp2 SH2 bind a phosphorylated Tyr568 RCM in of a netrin-dependent with as to is to RCM the results of in receptor and that Shp2 is to the phosphorylated RCM receptor in a that binding of the Shp2 SH2 to the Tyr568 phosphorylated a Y568F RCM tyrosine phosphorylation it is that RCM is a for Shp2 and that of to RCM is to the phosphorylation of tyrosine sites on is that Shp2 to signaling of Shp2 can the of the and Shp2 is to for cell and the of mammalian and in with can activated by to of the growth in cell Shp2 can potentially and and cell an on cell Shp2 a on the growth and to in to of Shp2 to RCM a on the of cell in to of Tyr568 phosphorylation in is in C. the of the RCM Y568F was elegans UNC-5 UNC-5 a reduced to the of null to wild type of in the UNC-5 and wild type that the of signaling in a vivo. is in receptor the growth receptor growth in C. C. C. for growth receptor that and of mutant in of mutant These results the that receptor in such that the of multiple signaling required for We are in the of multiple tyrosine to UNC-5 to the of UNC-5 multiple phosphorylation sites to null results to the mutants, the a reduced to the of null results that the UNC-5 receptor and its mammalian RCM are tyrosine phosphorylated in a that is on of a tyrosine in RCM a binding for the SH2 of the Shp2 tyrosine These that tyrosine phosphorylation is in UNC-5 signaling and the of cell growth in the are to by and repulsive guidance proteins that in of the and of receptors for guidance and and for the of the are of the deleted in colorectal and UNC-5 receptors and are required for the of growth by in of in the in of that are to a in UNC-5 as of are required for the repulsive of the C. the of UNC-5 in that from an UNC-6/netrin results in to that of UNC-5 in that to to to from the in an manner C. to was to by of UNC-5 in that the of and more of in C. from the UNC-6/netrin to a than of in UNC-5 receptors mediate repulsive to UNC-6/netrin Furthermore, is required for the of receptors in of the UNC-5 the mammalian and a and type by a cytoplasmic a by a domain to a of and a domain A binding was the and domain of cytoplasmic of guidance receptors are repulsive A receptor of a and an cytoplasmic domain a repulsive to the netrin-1 in a that the cytoplasmic domain the of growth to the netrin-1 of cytoplasmic signaling to the that the of a growth to a guidance cue on the of the in is the of by the the signaling for the and UNC-5 receptors are C. of growth induced by UNC-5 as as to required for axon and an a UNC-5 and the of and are proteins required for axon guidance in and on the of UNC-5 We that UNC-5 receptors are tyrosine phosphorylated in and tyrosine phosphorylation can enhanced by phosphorylation in the domain is and to bind with the Shp2 tyrosine phosphatase in and in vivo. to cell growth and more signaling in the of cell and in the of such as the the of receptor tyrosine such as axon guidance and in the mammalian as as the of and the of that the Furthermore, the C. elegans receptor cell receptor signaling the and can in the of growth and in the of from that on the cytoplasmic of receptors activated in with receptor tyrosine can bind SH2 domain proteins and can the in SH2 proteins such as and Shp2 tyrosine phosphorylation as a in cell and axon to receptors with tyrosine kinase a of receptors with tyrosine and tyrosine phosphorylation to SH2 domain proteins and for with cytoplasmic tyrosine the activated creating binding sites for the SH2 of that a of guidance kinase as for tyrosine and by tyrosine the repulsive effects of the on of the can phosphorylated on multiple tyrosine residues by the tyrosine kinase of of the tyrosine phosphorylation sites the a receptor that of tyrosine phosphorylation is to the of a receptor is tyrosine phosphorylated and the SH2 domain of the in a that for the of receptors mediate the effects of the guidance tyrosine phosphorylated in the an and cytoplasmic signaling tyrosine kinase that phosphorylation results from an associated tyrosine of tyrosine phosphorylation in axon guidance in is by the that tyrosine are in of from cell to axon guidance and in that tyrosine and are of repulsive signaling results that of the UNC-5 of guidance receptors are for tyrosine phosphorylation in of in and in at the is the signaling activated by the receptors and is phosphorylation the that kinase We find that the netrin-1 UNC-5 and are both phosphorylated on tyrosine in C. elegans and that the tyrosine phosphorylation of UNC-5 in is on UNC-5 to multiple tyrosine phosphorylation sites and it is that the tyrosine phosphorylation of UNC-5 in an unc-6 null mutant of C. is to phosphorylation sites a on as as is the of UNC-5 on it is that for UNC-5 that its to to A for UNC-5 is a of that is required to the of C. in growth guidance to a growth receptor and is a potential for UNC-5 by its to These are to the of UNC-5 tyrosine by that with tyrosine phosphorylation a reduced to null of C. These results suggest that tyrosine phosphorylation is a of UNC-5 and the that tyrosine phosphorylation is for UNC-5 in vivo. that UNC-5 tyrosine phosphorylation is the that mammalian RCM is tyrosine phosphorylated in the embryonic mouse that UNC-5 is in HEK-293 transfected cells, RCM is phosphorylated stimulation both the and netrin-stimulated tyrosine phosphorylation is enhanced by the of an activated Src tyrosine are for the RCM tyrosine phosphorylation in HEK-293 to in by a such as an in cell RCM phosphorylation by a tyrosine kinase is activated in HEK-293 cells. of the tyrosine kinase that UNC-5 in to the that UNC-5 and RCM elegans and the mouse that phosphorylation is a UNC-5 phosphorylation tyrosine and of proteins These that a tyrosine the domain is of the potential tyrosine phosphorylation sites in of RCM Tyr568 an SH2 and Shp2 SH2 bind a phosphorylated Tyr568 RCM in of a netrin-dependent with as to is to RCM the results of in receptor and that Shp2 is to the phosphorylated RCM receptor in a that binding of the Shp2 SH2 to the Tyr568 phosphorylated a Y568F RCM tyrosine phosphorylation it is that RCM is a for Shp2 and that of to RCM is to the phosphorylation of tyrosine sites on is that Shp2 to signaling of Shp2 can the of the and Shp2 is to for cell and the of mammalian and in with can activated by to of the growth in cell Shp2 can potentially and and cell an on cell Shp2 a on the growth and to in to of Shp2 to RCM a on the of cell in to of Tyr568 phosphorylation in is in C. the of the RCM Y568F was elegans UNC-5 UNC-5 a reduced to the of null to wild type of in the UNC-5 and wild type that the of signaling in a vivo. is in receptor the growth receptor growth in C. C. C. for growth receptor that and of mutant in of mutant These results the that receptor in such that the of multiple signaling required for We are in the of multiple tyrosine to UNC-5 to the of UNC-5 multiple phosphorylation sites to null results to the mutants, the a reduced to the of null results that the UNC-5 receptor and its mammalian RCM are tyrosine phosphorylated in a that is on of a tyrosine in RCM a binding for the SH2 of the Shp2 tyrosine These that tyrosine phosphorylation is in UNC-5 signaling and the of cell to cell growth and more signaling in the of cell and in the of such as the the of receptor tyrosine such as axon guidance and in the mammalian as as the of and the of that the Furthermore, the C. elegans receptor cell receptor signaling the and can in the of growth and in the of from that on the cytoplasmic of receptors activated in with receptor tyrosine can bind SH2 domain proteins and can the in SH2 proteins such as and Shp2 tyrosine phosphorylation as a in cell and axon to receptors with tyrosine kinase a of receptors with tyrosine and tyrosine phosphorylation to SH2 domain proteins and for with cytoplasmic tyrosine the activated creating binding sites for the SH2 of that a of guidance kinase as for tyrosine and by tyrosine the repulsive effects of the on of the can phosphorylated on multiple tyrosine residues by the tyrosine kinase of of the tyrosine phosphorylation sites the a receptor that of tyrosine phosphorylation is to the of a receptor is tyrosine phosphorylated and the SH2 domain of the in a that for the of receptors mediate the effects of the guidance tyrosine phosphorylated in the an and cytoplasmic signaling tyrosine kinase that phosphorylation results from an associated tyrosine of tyrosine phosphorylation in axon guidance in is by the that tyrosine are in of from cell to axon guidance and in that tyrosine and are of repulsive signaling results that of the UNC-5 of guidance receptors are for tyrosine phosphorylation in vivo. of in and in at the is the signaling activated by the receptors and is phosphorylation the that kinase We find that the netrin-1 UNC-5 and are both phosphorylated on tyrosine in C. elegans and that the tyrosine phosphorylation of UNC-5 in is on UNC-5 to multiple tyrosine phosphorylation sites and it is that the tyrosine phosphorylation of UNC-5 in an unc-6 null mutant of C. is to phosphorylation sites a on as as is the of UNC-5 on it is that for UNC-5 that its to to A for UNC-5 is a of that is required to the of C. in growth guidance to a growth receptor and is a potential for UNC-5 by its to These are to the of UNC-5 tyrosine by that with tyrosine phosphorylation a reduced to null of C. These results suggest that tyrosine phosphorylation is a of UNC-5 and the that tyrosine phosphorylation is for UNC-5 in vivo. that UNC-5 tyrosine phosphorylation is the that mammalian RCM is tyrosine phosphorylated in the embryonic mouse that UNC-5 is in HEK-293 transfected cells, RCM is phosphorylated stimulation both the and netrin-stimulated tyrosine phosphorylation is enhanced by the of an activated Src tyrosine are for the RCM tyrosine phosphorylation in HEK-293 to in by a such as an in cell RCM phosphorylation by a tyrosine kinase is activated in HEK-293 cells. of the tyrosine kinase that UNC-5 in to the that UNC-5 and RCM elegans and the mouse that phosphorylation is a UNC-5 phosphorylation tyrosine and of proteins These that a tyrosine the domain is of the potential tyrosine phosphorylation sites in of RCM Tyr568 an SH2 and Shp2 SH2 bind a phosphorylated Tyr568 RCM in of a netrin-dependent with as to is to RCM the results of in receptor and that Shp2 is to the phosphorylated RCM receptor in a that binding of the Shp2 SH2 to the Tyr568 phosphorylated a Y568F RCM tyrosine phosphorylation it is that RCM is a for Shp2 and that of to RCM is to the phosphorylation of tyrosine sites on is that Shp2 to signaling of Shp2 can the of the and Shp2 is to for cell and the of mammalian and in with can activated by to of the growth in cell Shp2 can potentially and and cell an on cell Shp2 a on the growth and to in to of Shp2 to RCM a on the of cell in to of Tyr568 phosphorylation in is in C. the of the RCM Y568F was elegans UNC-5 UNC-5 a reduced to the of null to wild type of in the UNC-5 and wild type that the of signaling in a vivo. is in receptor the growth receptor growth in C. C. C. for growth receptor that and of mutant in of mutant These results the that receptor in such that the of multiple signaling required for We are in the of multiple tyrosine to UNC-5 to the of UNC-5 multiple phosphorylation sites to null results to the mutants, the a reduced to the of null results that the UNC-5 receptor and its mammalian RCM are tyrosine phosphorylated in a that is on of a tyrosine in RCM a binding for the SH2 of the Shp2 tyrosine These that tyrosine phosphorylation is in UNC-5 signaling and the of cell of in and in at the is the signaling activated by the receptors and is phosphorylation the that kinase We find that the netrin-1 UNC-5 and are both phosphorylated on tyrosine in C. elegans and that the tyrosine phosphorylation of UNC-5 in is on UNC-5 to multiple tyrosine phosphorylation sites and it is that the tyrosine phosphorylation of UNC-5 in an unc-6 null mutant of C. is to phosphorylation sites a on as as is the of UNC-5 on it is that for UNC-5 that its to to A for UNC-5 is a of that is required to the of C. in growth guidance to a growth receptor and is a potential for UNC-5 by its to These are to the of UNC-5 tyrosine by that with tyrosine phosphorylation a reduced to null of C. These results suggest that tyrosine phosphorylation is a of UNC-5 and the that tyrosine phosphorylation is for UNC-5 in vivo. that UNC-5 tyrosine phosphorylation is the that mammalian RCM is tyrosine phosphorylated in the embryonic mouse that UNC-5 is in HEK-293 transfected cells, RCM is phosphorylated stimulation both the and netrin-stimulated tyrosine phosphorylation is enhanced by the of an activated Src tyrosine are for the RCM tyrosine phosphorylation in HEK-293 to in by a such as an in cell RCM phosphorylation by a tyrosine kinase is activated in HEK-293 cells. of the tyrosine kinase that UNC-5 in to the that UNC-5 and RCM elegans and the mouse that phosphorylation is a UNC-5 phosphorylation tyrosine and of proteins These that a tyrosine the domain is of the potential tyrosine phosphorylation sites in of RCM Tyr568 an SH2 and Shp2 SH2 bind a phosphorylated Tyr568 RCM in of a netrin-dependent with as to is to RCM the results of in receptor and that Shp2 is to the phosphorylated RCM receptor in a that binding of the Shp2 SH2 to the Tyr568 phosphorylated a Y568F RCM tyrosine phosphorylation it is that RCM is a for Shp2 and that of to RCM is to the phosphorylation of tyrosine sites on is that Shp2 to signaling of Shp2 can the of the and Shp2 is to for cell and the of mammalian and in with can activated by to of the growth in cell Shp2 can potentially and and cell an on cell Shp2 a on the growth and to in to of Shp2 to RCM a on the of cell in to of Tyr568 phosphorylation in is in C. the of the RCM Y568F was elegans UNC-5 UNC-5 a reduced to the of null to wild type of in the UNC-5 and wild type that the of signaling in a vivo. is in receptor the growth receptor growth in C. C. C. for growth receptor that and of mutant in of mutant These results the that receptor in such that the of multiple signaling required for We are in the of multiple tyrosine to UNC-5 to the of UNC-5 multiple phosphorylation sites to null results to the mutants, the a reduced to the of null results that the UNC-5 receptor and its mammalian RCM are tyrosine phosphorylated in a that is on of a tyrosine in RCM a binding for the SH2 of the Shp2 tyrosine These that tyrosine phosphorylation is in UNC-5 signaling and the of cell of in and in at the is the signaling activated by the receptors and is phosphorylation the that kinase We find that the netrin-1 UNC-5 and are both phosphorylated on tyrosine in C. elegans and that the tyrosine phosphorylation of UNC-5 in is on UNC-5 to multiple tyrosine phosphorylation sites and it is that the tyrosine phosphorylation of UNC-5 in an unc-6 null mutant of C. is to phosphorylation sites a on as as is the of UNC-5 on it is that for UNC-5 that its to to A for UNC-5 is a of that is required to the of C. in growth guidance to a growth receptor and is a potential for UNC-5 by its to These are to the of UNC-5 tyrosine by that with tyrosine phosphorylation a reduced to null of C. These results suggest that tyrosine phosphorylation is a of UNC-5 and the that tyrosine phosphorylation is for UNC-5 in vivo. that UNC-5 tyrosine phosphorylation is the that mammalian RCM is tyrosine phosphorylated in the embryonic mouse that UNC-5 is in HEK-293 transfected cells, RCM is phosphorylated stimulation both the and netrin-stimulated tyrosine phosphorylation is enhanced by the of an activated Src tyrosine are for the RCM tyrosine phosphorylation in HEK-293 to in by a such as an in cell RCM phosphorylation by a tyrosine kinase is activated in HEK-293 cells. of the tyrosine kinase that UNC-5 in to the that UNC-5 and RCM elegans and the mouse that phosphorylation is a UNC-5 phosphorylation tyrosine and of proteins These that a tyrosine the domain is of the potential tyrosine phosphorylation sites in at the is the signaling activated by the receptors and is phosphorylation the that kinase We find that the netrin-1 UNC-5 and are both phosphorylated on tyrosine in C. elegans and that the tyrosine phosphorylation of UNC-5 in is on UNC-5 to multiple tyrosine phosphorylation sites and it is that the tyrosine phosphorylation of UNC-5 in an unc-6 null mutant of C. is to phosphorylation sites a on as as is the of UNC-5 on it is that for UNC-5 that its to to A for UNC-5 is a of that is required to the of C. in growth guidance to a growth receptor and is a potential for UNC-5 by its to These are to the of UNC-5 tyrosine by that with tyrosine phosphorylation a reduced to null of C. These results suggest that tyrosine phosphorylation is a of UNC-5 and the that tyrosine phosphorylation is for UNC-5 in vivo. that UNC-5 tyrosine phosphorylation is the that mammalian RCM is tyrosine phosphorylated in the embryonic mouse that UNC-5 is in HEK-293 transfected cells, RCM is phosphorylated stimulation both the and netrin-stimulated tyrosine phosphorylation is enhanced by the of an activated Src tyrosine are for the RCM tyrosine phosphorylation in HEK-293 to in by a such as an in cell RCM phosphorylation by a tyrosine kinase is activated in HEK-293 cells. of the tyrosine kinase that UNC-5 in to the that UNC-5 and RCM elegans and the mouse that phosphorylation is a UNC-5 phosphorylation tyrosine and of proteins These that a tyrosine the domain is of the potential tyrosine phosphorylation sites in of RCM Tyr568 an SH2 and Shp2 SH2 bind a phosphorylated Tyr568 RCM in of a netrin-dependent with as to is to RCM the results of in receptor and that Shp2 is to the phosphorylated RCM receptor in a that binding of the Shp2 SH2 to the Tyr568 phosphorylated a Y568F RCM tyrosine phosphorylation it is that RCM is a for Shp2 and that of to RCM is to the phosphorylation of tyrosine sites on is that Shp2 to signaling of Shp2 can the of the and Shp2 is to for cell and the of mammalian and in with can activated by to of the growth in cell Shp2 can potentially and and cell an on cell Shp2 a on the growth and to in to of Shp2 to RCM a on the of cell in to of Tyr568 phosphorylation in is in C. the of the RCM Y568F was elegans UNC-5 UNC-5 a reduced to the of null to wild type of in the UNC-5 and wild type that the of signaling in a vivo. is in receptor the growth receptor growth in C. C. C. for growth receptor that and of mutant in of mutant These results the that receptor in such that the of multiple signaling required for We are in the of multiple tyrosine to UNC-5 to the of UNC-5 multiple phosphorylation sites to null results to the mutants, the a reduced to the of null results that the UNC-5 receptor and its mammalian RCM are tyrosine phosphorylated in a that is on of a tyrosine in RCM a binding for the SH2 of the Shp2 tyrosine These that tyrosine phosphorylation is in UNC-5 signaling and the of cell and Shp2 SH2 bind a phosphorylated Tyr568 RCM in of a netrin-dependent with as to is to RCM the results of in receptor and that Shp2 is to the phosphorylated RCM receptor in a that binding of the Shp2 SH2 to the Tyr568 phosphorylated a Y568F RCM tyrosine phosphorylation it is that RCM is a for Shp2 and that of to RCM is to the phosphorylation of tyrosine sites on is that Shp2 to signaling of Shp2 can the of the and Shp2 is to for cell and the of mammalian and in with can activated by to of the growth in cell Shp2 can potentially and and cell an on cell Shp2 a on the growth and to in to of Shp2 to RCM a on the of cell in to of Tyr568 phosphorylation in is in C. the of the RCM Y568F was elegans UNC-5 UNC-5 a reduced to the of null to wild type of in the UNC-5 and wild type that the of signaling in a vivo. is in receptor the growth receptor growth in C. C. C. for growth receptor that and of mutant in of mutant These results the that receptor in such that the of multiple signaling required for We are in the of multiple tyrosine to UNC-5 to the of UNC-5 multiple phosphorylation sites to null results to the mutants, the a reduced to the of null results that the UNC-5 receptor and its mammalian RCM are tyrosine phosphorylated in a that is on of a tyrosine in RCM a binding for the SH2 of the Shp2 tyrosine These that tyrosine phosphorylation is in UNC-5 signaling and the of cell We and for on for netrin-1 and and for a netrin-1 cell for and for with and for

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.