title: Small molecule inhibitors of the Pyk2 and FAK kinases modulate chemoattractant-induced migration, adhesion and Akt activation in follicular and marginal zone B cells.
abstract: B-lymphocytes produce protective antibodies but also contribute to autoimmunity. In particular, marginal zone (MZ) B cells recognize both microbial components and self-antigens. B cell trafficking is critical for B cell activation and is controlled by chemoattactants such as CXCL13 and sphingosine 1-phosphate (S1P). The related tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase (Pyk2) regulate cell migration and adhesion but their roles in B cells are not fully understood. Using a novel Pyk2-selective inhibitor described herein (PF-719), as well as a FAK-selective inhibitor, we show that both Pyk2 and FAK are important for CXCL13- and S1P-induced migration of B-2 cells and MZ B cells. In contrast, LFA-1-mediated adhesion required only Pyk2 whereas activation of the Akt pro-survival kinase required FAK but not Pyk2. Thus Pyk2 and FAK mediate critical processes in B cells and these inhibitors can be used to further elucidate their functions in B cells.
authors.affiliation: Department of Microbiology & Immunology, I(3) and CELL Research Groups, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. kathytse.wk@gmail.com
authors.forename: Kathy W K
authors.initials: KW
authors.lastname: Tse
authors.forename: Kevin B L
authors.initials: KB
authors.lastname: Lin
authors.forename: May
authors.initials: M
authors.lastname: Dang-Lawson
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Gary E
authors.initials: GE
authors.lastname: Aspnes
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gold
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D054382:Chemokine CXCL13 / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology*; D062366:para-Aminobenzoates
chemical_list: C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D054382:Chemokine CXCL13; D002630:Chemotactic Factors; D008246:Lysophospholipids; C573151:PF-719; D011743:Pyrimidines; D015363:Quinolones; D013450:Sulfones; D062366:para-Aminobenzoates; C060506:sphingosine 1-phosphate; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496053:Ptk2b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D010129:4-Aminobenzoic Acid