Identification of phospholipase C gamma1 as a protein tyrosine phosphatase mu substrate that regulates cell migration.
The receptor protein tyrosine phosphatase PTPµ has a cell-adhesion molecule-like extracellular segment and a catalytically active intracellular segment. This structure gives PTPµ the ability to transduce signals in response to cell-cell adhesion. Full-length PTPµ is down-regulated in glioma cells by proteolysis which is linked to increased migration of these cells in the brain. To gain insight into the substrates PTPµ may be dephosphorylating to suppress glioma cell migration, we used a substrate trapping method to identify PTPµ substrates in tumor cell lines. We identified both PKCδ and PLCγ1 as PTPµ substrates. As PLCγ1 activation is linked to increased invasion of cancer cells, we set out to determine whether PTPµ may be upstream of PLCγ1 in regulating glioma cell migration. We conducted brain slice assays using U87-MG human glioma cells in which PTPµ expression was reduced by shRNA to induce migration. Treatment of the same cells with PTPµ shRNA and a PLCγ1 inhibitor prevented migration of the cells within the brain slice. These data suggest that PLCγ1 is downstream of PTPµ and that dephosphorylation of PLCγ1 is likely to be a major pathway through which PTPµ suppresses glioma cell migration.
Phillips-Mason
Polly J
PJ
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106-4960, USA.
Kaur
Harpreet
H
Burden-Gulley
Susan M
SM
Craig
Sonya E L
SE
Brady-Kalnay
Susann M
SM
D001932:Brain Neoplasms / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D005910:Glioma / Q000378:metabolism; D006801:Humans; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D012333:RNA, Messenger; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D051966:Phospholipase C gamma