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4 Integrins that Signal Through Src Family Kinases1
Department of Laboratory Medicine, University of California, San Francisco, CA 94143
There is mounting evidence that 
4 (CD49d) integrins
are involved in neutrophil recruitment and function during inflammatory
responses. We report that all resting murine neutrophils derived from
bone marrow or peripheral blood express easily detectable levels of
4 integrins on their surface. These 4
integrins were functional, as demonstrated by stimulation of
respiratory burst when neutrophils adhered to surfaces coated with the
murine vascular cell adhesion molecule-1 (mVCAM-1). Adhesion occurred
via 4 integrins, as preincubation of neutrophils with an
anti-4-specific Ab inhibited attachment to mVCAM-1.
Direct cross-linking of the 4 integrin subunit by
surface-bound mAbs also elicited superoxide release and release of the
secondary granule marker, lactoferrin. The functional responses that
occurred downstream of 4 integrin cross-linking required
signaling by Src family kinases. Neutrophils derived from
hck-/-fgr-/-lyn-/-
triple-knockout or
hck-/-fgr-/-
double-knockout mice failed to undergo respiratory burst when plated on
mVCAM-1. Triple mutant neutrophils were also defective in release of
both superoxide and lactoferrin when plated on surfaces coated with
mAbs directed against 4. Correlated with impaired
4-induced functional responses, triple-mutant
neutrophils also failed to spread and tightly adhere to
anti-4 mAb-coated surfaces. This is the first direct
evidence that functional 4 integrins are expressed by
murine PMNs, and that these surface molecules can mediate cellular
responses such as tight adhesion, spreading, sustained respiratory
burst, and specific granule release in vitro. Moreover the
4 integrins, like all other integrins tested, use the
Src family kinases to transduce intracellular
signals.
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