Small molecule inhibitors of the Pyk2 and FAK kinases modulate chemoattractant-induced migration, adhesion and Akt activation in follicular and marginal zone B cells

Cell Immunol. 2012 Jan-Feb;275(1-2):47-54. doi: 10.1016/j.cellimm.2012.03.002. Epub 2012 Mar 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminobenzoic Acid / pharmacology
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / enzymology
  • Cell Adhesion / drug effects
  • Cell Line
  • Chemokine CXCL13 / pharmacology
  • Chemotactic Factors / pharmacology
  • Chemotaxis / drug effects*
  • Enzyme Activation / drug effects
  • Focal Adhesion Kinase 2 / antagonists & inhibitors*
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Lysophospholipids / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyrimidines / pharmacology*
  • Quinolones / pharmacology*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Sulfones / pharmacology*
  • para-Aminobenzoates*

Substances

  • 6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one
  • Chemokine CXCL13
  • Chemotactic Factors
  • Lysophospholipids
  • PF-719
  • Pyrimidines
  • Quinolones
  • Sulfones
  • para-Aminobenzoates
  • sphingosine 1-phosphate
  • Focal Adhesion Kinase 2
  • Focal Adhesion Protein-Tyrosine Kinases
  • Ptk2b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Sphingosine
  • 4-Aminobenzoic Acid