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Query: UMLS:C0344329 (
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28,634
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Netrin-1 is a bifunctional guidance cue that directs migrating neurons and axons based on specific receptors expressed on the cell surface. Attraction occurs through the receptor Deleted in Colorectal Cancer (DCC) and repulsion occurs through a receptor complex of DCC and UNC5H, the vertebrate homolog to Caenorhabditis elegans UNC-5, but how the specific surface expression of these receptors is achieved remains unknown. Here, we demonstrate that surface expression of
UNC5H1
is regulated in neurons by protein interacting with C kinase-1 (PICK1) and protein kinase C (PKC), and show that one mechanism by which cells control their response to netrin-1 is by changing the surface availability of receptors. We identified PICK1 as a binding partner for
UNC5H1
using the yeast two-hybrid system and found that the extreme three C-terminal amino acids of
UNC5H1
interact with the PSD-95/Dlg/ZO-1 (PDZ) domain of PICK1. Coexpression of
UNC5H1
and PICK1 in heterologous cells results in the recruitment of PICK1 to
UNC5H1
clusters. Endogenous
UNC5H1
and PICK1 coimmunoprecipitate from extracts of cultured hippocampal neurons and P4 cortices, and immunohistochemistry shows that
UNC5H1
, PICK1, and PKC are all present in growth cones. PKC activation induces the formation of
UNC5H1
/PICK1/PKC complexes and leads to the specific removal of
UNC5H1
, but not DCC, from the surface of neurons and growth cones via a PICK1/PKC-dependent mechanism. Lastly, we demonstrate that activating PKC, which decreases surface expression of
UNC5H1
, inhibits netrin-1-dependent
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of hippocampal growth cones. Together, our results suggest that by regulating the surface expression of UNC5Hs, an axon can modulate its repellent response to netrin-1.
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PMID:Surface expression of the netrin receptor UNC5H1 is regulated through a protein kinase C-interacting protein/protein kinase-dependent mechanism. 1467 91
