The Tyrosine Kinase Pyk2 Promotes Migration and Invasion of Glioma Cells

Abstract

Glioblastoma multiforme is extraordinarily aggressive due to the propensity of cells to migrate away from the tumor core into the surrounding normal brain. In this report, we investigated the role of proline-rich tyrosine kinase 2 (Pyk2) and FAK with regard to influencing glioma cell phenotypes. Expression of Pyk2 stimulated glioma cell migration, whereas expression of FAK inhibited glioma cell migration and stimulated cell cycle progression. Pyk2 autophosphorylation was necessary, but not sufficient, to stimulate cellular migration. The N-terminal domain of Pyk2 is required for stimulation of migration as an N-terminally deleted variant of Pyk2 failed to stimulate migration, whereas expression of an autonomous Pyk2 N-terminal domain inhibited cell migration. Substitution of the C-terminal domain of Pyk2 with the corresponding domain of FAK stimulated cell migration as effectively as wild-type Pyk2; however, substitution of the N-terminal domain of Pyk2 with that of FAK inhibited cell migration, substantiating that the N-terminal domain of Pyk2 was required to stimulate migration. Silencing of Pyk2 expression by RNA interference significantly inhibited glioma migration. Cell migration was restored on re-expression of Pyk2, but expression of FAK in Pyk2 knockdown cells failed to restore migration. We conclude that Pyk2 plays a central role in the migratory behavior of glioblastomas.

Essential role of Pyk2 and Src kinase activation in neuropeptide-induced proliferation of small cell lung cancer cells

“…Furthermore, Pyk2 is involved in the signal transduction of CXCL12-induced metastasis of breast cancer cells (Fernandis et al, 2004). In glioblastoma cells, Pyk2 activity is significantly correlated with migratory potential, and Pyk2 is implicated in the development of osteolytic bone metastases activated by ligation of aVb3 integrin (Teti et al, 2002;Lipinski et al, 2005). In this report we describe an essential role of Pyk2 and Src kinases for Ca 2 þ -dependent proliferation and survival of SCLC cells.…”

Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

“…Moreover, malignant gliomas remain poorly responsive to multimodal therapeutic interventions, including radiotherapy and chemotherapy (Legler et al, 1999). The resistance of glioblastoma multiforme to treatments is related to its cellular heterogeneity (Misra et al, 2000) and the exceptional migratory nature of the tumor cells, which are able to diffusely infiltrate normal brain tissue (Lipinski et al, 2003). Due to this poor prognosis and the absence of successful therapeutics for glioma patients, new therapeutic paradigms for the treatment of malignant gliomas need to be explored.…”

PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition

“…The first one (No.1) was purchased from Sigma (TRCN00000231519), whereas the second one (No. 2) was described previously 66 . The PYK2 shRNAs were cloned into the pLKO.1-puro lentiviral vector.…”