PubMed Journals: J Biol Chem

  Source:		PMID: 9099755

    		J Biol Chem. 1997 Apr 18;272(16):10957-67.
			Autophosphorylation of activation loop tyrosines
			regulates signaling by the TRK
			nerve growth factor receptor.

			Cunningham ME(1), Stephens RM, Kaplan DR,
			Greene LA.

			Author Information
			(1) Department of Pathology and Center of
			Neurobiology and Behavior, College of Physicians
			and Surgeons, Columbia University, New York,
			New York 10032, USA.

			Many receptor tyrosine kinases possess an
			"activation loop" containing three similarly
			placed tyrosine autophosphorylation sites.
			To examine their roles in the TRK NGF receptor,
			these residues (Tyr-670, Tyr-674, and Tyr-675)
			were mutated singly and in all combinations
			to phenylalanine and stably expressed in
			Trk-deficient PC12nnr5 cells. All mutant
			receptors showed significantly diminished
			nerve growth factor (NGF)-stimulated
			autophosphorylation, indicating impaired
			catalytic activity. NGF-induced neurite
			outgrowth exhibited dose-responsive behavior
			when transfectants were compared by relative
			receptor expression and exhibited a functional
			hierarchy: wild type > Y670F >/= Y674F >>
			Y675F >/= YY670/674FF = YY670/675FF >> YY674/675FF
			> YYY670/674/675FFF. NGF-induced tyrosine
			phosphorylation of Shc, ERKs, and SNT and
			immediate early gene inductions generally
			paralleled neurogenic potential. However,
			activation of phosphatidylinositol 3'-kinase
			and tyrosine phosphorylation of phospholipase
			Cgamma-1 was essentially abolished. The
			latter effect appears due to selective inability
			of the mutated TRKs to autophosphorylate
			the tyrosine residue (Tyr-785) required
			for binding phospholipase Cgamma-1 and indicates
			that the "activation loop" tyrosines participate
			in NGF-dependent changes in receptor conformation.
			Our findings stress the importance that
			expression levels play in assessing the
			consequences of receptor mutations and that
			all three activation loop tyrosines have
			roles regulating both overall and specific
			NGF-mediated signaling through TRK.

			PMID: 9099755 [Indexed for MEDLINE]

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