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* Howard Hughes Medical Institute, This paper presents evidence that a member
of the L1 family of ankyrin-binding cell adhesion molecules is a substrate for protein tyrosine kinase(s) and
phosphatase(s), identifies the highly conserved FIGQY
tyrosine in the cytoplasmic domain as the principal site
of phosphorylation, and demonstrates that phosphorylation of the FIGQY tyrosine abolishes ankyrin-binding activity. Neurofascin expressed in neuroblastoma
cells is subject to tyrosine phosphorylation after activation of tyrosine kinases by NGF or bFGF or inactivation of tyrosine phosphatases with vanadate or dephostatin. Furthermore, both neurofascin and the related
molecule Nr-CAM are tyrosine phosphorylated in a developmentally regulated pattern in rat brain. The
FIGQY sequence is present in the cytoplasmic domains
of all members of the L1 family of neural cell adhesion
molecules. Phosphorylation of the FIGQY tyrosine
abolishes ankyrin binding, as determined by coimmunoprecipitation of endogenous ankyrin and in vitro
ankyrin-binding assays. Measurements of fluorescence
recovery after photobleaching demonstrate that phosphorylation of the FIGQY tyrosine also increases lateral mobility of neurofascin expressed in neuroblastoma cells to the same extent as removal of the
cytoplasmic domain. Ankyrin binding, therefore, appears to regulate the dynamic behavior of neurofascin
and is the target for regulation by tyrosine phosphorylation in response to external signals. These findings
suggest that tyrosine phosphorylation at the FIGQY
site represents a highly conserved mechanism, used by
the entire class of L1-related cell adhesion molecules,
for regulation of ankyrin-dependent connections to the
spectrin skeleton.
Department of Cell Biology, and Department of Biochemistry, § Duke University Medical
Center, Durham, North Carolina 27710
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