Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr.
While beta 2 integrin ligand-receptor recognition interactions are well characterized, less is known about how these events trigger signal transduction cascades to regulate the transition from tethering to firm adhesion, spreading, and transendothelial migration. We have identified critical positive and negative regulatory components of this cascade in monocytes. Whereas the Syk tyrosine kinase is essential for beta 2 integrin signaling and cell spreading, the Src family kinase Fgr is a negative regulator of this pathway. Fgr selectively inhibits beta 2 but not beta 1 integrin signaling and Syk kinase function via a direct association between the Fgr SH2 domain and Syk tyrosine Y342. The inhibitory effects of Fgr are independent of its kinase activity, are dose dependent, and can be overcome by chemokines and inflammatory mediators.
Vines
C M
CM
Department of Pathology and Cancer Research Facility, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Potter
J W
JW
Xu
Y
Y
Geahlen
R L
RL
Costello
P S
PS
Tybulewicz
V L
VL
Lowell
C A
CA
Chang
P W
PW
Gresham
H D
HD
Willman
C L
CL
D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D048429:Cell Size; D002478:Cells, Cultured; D018925:Chemokines / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051572:Proto-Oncogene Proteins c-hck; D015398:Signal Transduction; D000072377:Syk Kinase; D014162:Transfection; D018909:src Homology Domains; D019061:src-Family Kinases
D018821:CD18 Antigens; D018925:Chemokines; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases