Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas - PubMed (original) (raw)

Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas

L P Weng et al. Genes Cells. 1999 Mar.

Free article

Abstract

Background: LAR is a transmembrane receptor-like protein tyrosine phosphatase (PTP). Genetic studies of Drosophila LAR suggest that LAR may function to regulate cell adhesions or adhesion-mediated signal transduction. The over-expression of LAR in mammalian tissue culture cells does not affect cell adhesion but induces caspase-dependent apoptosis. This study investigates molecular mechanisms of LAR-induced apoptosis by searching for in vivo substrates of LAR which are responsible for LAR-induced apoptosis.

Results: The over-expression of LAR in tissue culture cells specifically decreased the steady state protein level of p130Cas, a multifunctional signal assembly protein in signal transduction, by reducing the tyrosine phosphorylation and protein stability of p130Cas. The reduction of p130Cas protein level could be inhibited by tyrosine phosphatase inhibitors. Phosphatase domain-deleted mutant LARs had no effect on p130Cas. LAR also preferentially dephosphorylated p130Cas in vitro. Subcellularly, LAR and p130Cas were co-localized along stress fibres and at focal adhesions. LAR over-expression eliminated p130Cas from focal adhesions without affecting focal adhesion assembly. Restoring the level of p130Cas alleviated LAR-induced apoptosis.

Conclusions: p130Cas is an in vivo substrate of LAR. LAR specifically dephosphorylates and destabilizes p130Cas and may play a role in regulating cell adhesion-mediated cell survival. The function of p130Cas in focal adhesions may not be to regulate focal adhesion assembly and cell adhesion but rather to transduce the cell adhesion-generated signals which are essential for cell survival.

PubMed Disclaimer

Cited by

Receptor type protein tyrosine phosphatases (RPTPs) - roles in signal transduction and human disease.
Xu Y, Fisher GJ. Xu Y, et al. J Cell Commun Signal. 2012 Aug;6(3):125-38. doi: 10.1007/s12079-012-0171-5. Epub 2012 Aug 1. J Cell Commun Signal. 2012. PMID: 22851429 Free PMC article.
CAS proteins in normal and pathological cell growth control.
Tikhmyanova N, Little JL, Golemis EA. Tikhmyanova N, et al. Cell Mol Life Sci. 2010 Apr;67(7):1025-48. doi: 10.1007/s00018-009-0213-1. Epub 2009 Nov 25. Cell Mol Life Sci. 2010. PMID: 19937461 Free PMC article. Review.
PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration.
Zeng L, Si X, Yu WP, Le HT, Ng KP, Teng RM, Ryan K, Wang DZ, Ponniah S, Pallen CJ. Zeng L, et al. J Cell Biol. 2003 Jan 6;160(1):137-46. doi: 10.1083/jcb.200206049. Epub 2003 Jan 6. J Cell Biol. 2003. PMID: 12515828 Free PMC article.
Acquisition of the metastatic phenotype is accompanied by H2O2-dependent activation of the p130Cas signaling complex.
Hempel N, Bartling TR, Mian B, Melendez JA. Hempel N, et al. Mol Cancer Res. 2013 Mar;11(3):303-12. doi: 10.1158/1541-7786.MCR-12-0478. Epub 2013 Jan 23. Mol Cancer Res. 2013. PMID: 23345605 Free PMC article.
Selective expression of CSPG receptors PTPσ and LAR in poorly regenerating reticulospinal neurons of lamprey.
Zhang G, Hu J, Li S, Huang L, Selzer ME. Zhang G, et al. J Comp Neurol. 2014 Jun 15;522(9):2209-29. doi: 10.1002/cne.23529. J Comp Neurol. 2014. PMID: 24357129 Free PMC article.

Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas - PubMed (original) (raw)