Essential role for focal adhesion kinase in regulating stress hematopoiesis.
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that has been extensively studied in fibroblasts; however its function in hematopoiesis remains an enigma. FAK is thought to be expressed in myeloid and erythroid progenitors, and its expression is enhanced in response to cytokines such as granu-locyte macrophage colony-stimulating factor. Furthermore, bone marrow cells cultured in granulocyte macrophage colony-stimulating factor show active migration and chemoattractant-induced polarization, which correlates with FAK induction. While loss of FAK in mice results in embryonic lethality, we have deleted FAK in the adult bone marrow. We show an essential role for FAK in regulating hemolytic, myelotoxic, as well as acute inflammatory stress responses in vivo. In vitro, loss of FAK in erythroid and myeloid progenitor's results in impaired cytokine induced growth and survival, as well as defects in the activation and expression of antiapoptotic proteins caspase 3 and Bcl-x(L). Additionally, reduced migration and adhesion of myeloid cells on extracellular matrix proteins, as well as impaired activation of Rac GTPase is also observed in the absence of FAK. Our studies reveal an essential role for FAK in integrating growth/survival and adhesion based functions in myeloid and erythroid cells predominantly under conditions of stress.
Vemula
Sasidhar
S
Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA. svemula@iupui.edu
Ramdas
Baskar
B
Hanneman
Philip
P
Martin
Joseph
J
Beggs
Hilary E
HE
Kapur
Reuben
R
D000199:Actins / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D017353:Gene Deletion; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D038042:Myelopoiesis / Q000187:drug effects; D010538:Peritonitis / Q000276:immunology / Q000473:pathology; D010659:Phenylhydrazines / Q000494:pharmacology; D013312:Stress, Physiological / Q000187:drug effects
D000199:Actins; D016207:Cytokines; D010659:Phenylhydrazines; C030299:phenylhydrazine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005472:Fluorouracil