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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2559-2568
A Mutation in the Extracellular Cysteine-Rich Repeat Region of the
 3 Subunit Activates Integrins
 IIb3 and V3
Hirokazu Kashiwagi,
Yoshiaki Tomiyama,
Seiji Tadokoro,
Shigenori Honda,
Masamichi Shiraga,
Hajime Mizutani,
Makoto Handa,
Yoshiyuki Kurata,
Yuji Matsuzawa, and
Sanford J. Shattil
From The Second Department of Internal Medicine, Osaka University
Medical School, and Department of Transfusion, Osaka University
Hospital, Osaka, Japan; the Blood Center, Keio University Hospital,
Tokyo, Japan; and the Department of Vascular Biology and Molecular and
Experimental Medicine, The Scripps Research Institute, La Jolla,
CA.
Inside-out signaling regulates the ligand-binding function of
integrins through changes in receptor affinity and/or avidity. For
example,  IIb 3 is in a
low-affinity/avidity state in resting platelets, and activation of the
receptor by platelet agonists enables fibrinogen to bind. In addition,
certain mutations and truncations of the integrin cytoplasmic tails are
associated with a high-affinity/avidity receptor. To further evaluate
the structural basis of integrin activation, stable Chinese hamster
ovary (CHO) cell transfectants were screened for high-affinity/avidity
variants of IIb3. One clone (AM-1)
expressed constitutively active IIb3, as evidenced by (1) binding of soluble fibrinogen and PAC1, a ligand-mimetic antiIIb3
antibody; and (2) fibrinogen-dependent cell aggregation. Sequence
analysis and mutant expression in 293 cells proved that a single amino
acid substitution in the cysteine-rich, extracellular portion of
3(T562N) was responsible for receptor activation. In
fact, T562N also activated V3, leading to
spontaneous binding of soluble fibrinogen to 293 cells. In contrast,
neither T562A nor T562Q activated IIb3,
suggesting that acquisition of asparagine at residue 562 was the
relevant variable. T562N also led to aberrant glycosylation of
3, but this was not responsible for the receptor
activation. The binding of soluble fibrinogen to
IIb3(T562N) was not sufficient to trigger
tyrosine phosphorylation of pp125FAK, indicating that
additional post-ligand binding events are required to activate this
protein tyrosine kinase during integrin signaling. These studies have
uncovered a novel gain-of-function mutation in a region of
3 intermediate between the ligand-binding region and the
cytoplasmic tail, and they suggest that this region is involved in
integrin structural changes during inside-out signaling.
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