Cortactin, a Lyn substrate, is a checkpoint molecule at the intersection of BCR and CXCR4 signalling pathway in chronic lymphocytic leukaemia cells

Abstract

Cortactin (CTTN) is a substrate of the Src kinase Lyn that is known to play an actin cytoskeletal regulatory role involved in cell migration and cancer progression following its phosphorylation at Y421. We recently demonstrated that Cortactin is overexpressed in patients with chronic lymphocytic leukaemia (CLL). This work was aimed at defining the functional role of Cortactin in these patients. We found that Cortactin is variably expressed in CLL patients both in the peripheral blood and lymph nodes and that its expression correlates with the release of matrix metalloproteinase 9 (MMP-9) and the motility of neoplastic cells. Cortactin knockdown, by siRNA, induced a reduction in MMP-9 release as well as a decrease of migration capability of leukaemic B cells in vitro, also after chemotactic stimulus. Furthermore, Cortactin phosphorylation was lowered by the Src kinase-inhibitor PP2 with a consequent decrease of MMP-9 release in culture medium. An impaired migration, as compared to control experiments without Cortactin knockdown, was observed following CXCL12 triggering. Reduced Cortactin expression and phosphorylation were also detected both in vivo and in vitro after treatment with Ibrutinib, a Btk inhibitor. Our results highlight the role of Cortactin in CLL as a check-point molecule between the BCR and CXCR4 signalling pathways.

In chronic lymphocytic leukaemia with complex karyotype, major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics

“…RASGRF1 has been found overexpressed in CLL and its activation was blocked by Bruton Tyrosine Kinase inhibitors (Liao et al , ). Cortactin binding protein 2 (CTTNBP2) is an actin binding protein and Lyn substrate that is up‐regulated in CLL patients and correlates to a poor prognosis, suggesting that this protein could be relevant in the pathogenesis and aggressiveness of the disease (Martini et al , ). Finally, reduced SLAMF1 levels have been associated with clinical and molecular markers of unfavourable prognosis.…”

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

“…Cells (5 × 10 5 for each assay) were prepared by cell lysis, subjected to sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS/PAGE), transferred to nitrocellulose membranes, as previously described [52], and immunostained with antibodies to p-STAT3 Tyr705, p-STAT3 Ser727, STAT3, PARP, JAK2 (Cell Signaling Technology Inc.; Danvers, MA, USA); p-SHP-1 Ser591, SHP-1 (Millipore; Billerica, MA, USA); p-Lyn Tyr396 (Epitomics Onc. ; Burlingame, CA, USA); Lyn (Santa Cruz Biotechnology; Dallas, TX, USA); α-Tubulin and β-Actin (Sigma-Aldrich).…”

Immunohistochemical Expression of Cortactin, E-Cadherin, and MDM2 Proteins in Solid Ameloblastoma versus Odontogenic Keratocyst (An immunohistochemical study)

“…Cortactin overexpression was found in different cancers such as head and neck squamous carcinoma, breast, hepatocellular carcinoma, and bladder cancer, and linked with reduced patientprognosis and decline survival. Its overexpression has been corresponding to advanced clinic stage and poor out come in several tumors (11)(12)(13) .…”