 |
PDBsum entry 3zdt
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Phosphatidylinositol 4,5-Bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes.
|
|
|
Authors
|
|
G.M.Goñi,
C.Epifano,
J.Boskovic,
M.Camacho-Artacho,
J.Zhou,
A.Bronowska,
M.T.Martín,
M.J.Eck,
L.Kremer,
F.Gräter,
F.L.Gervasio,
M.Perez-Moreno,
D.Lietha.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2014,
111,
E3177.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase (NRTK) with key
roles in integrating growth and cell matrix adhesion signals, and FAK is a major
driver of invasion and metastasis in cancer. Cell adhesion via integrin
receptors is well known to trigger FAK signaling, and many of the players
involved are known; however, mechanistically, FAK activation is not understood.
Here, using a multidisciplinary approach, including biochemical, biophysical,
structural, computational, and cell biology approaches, we provide a detailed
view of a multistep activation mechanism of FAK initiated by
phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Interestingly, the mechanism
differs from canonical NRTK activation and is tailored to the dual catalytic and
scaffolding function of FAK. We find PI(4,5)P2 induces clustering of FAK on the
lipid bilayer by binding a basic region in the regulatory 4.1, ezrin, radixin,
moesin homology (FERM) domain. In these clusters, PI(4,5)P2 induces a partially
open FAK conformation where the autophosphorylation site is exposed,
facilitating efficient autophosphorylation and subsequent Src recruitment.
However, PI(4,5)P2 does not release autoinhibitory interactions; rather, Src
phosphorylation of the activation loop in FAK results in release of the
FERM/kinase tether and full catalytic activation. We propose that PI(4,5)P2 and
its generation in focal adhesions by the enzyme phosphatidylinositol 4-phosphate
5-kinase type Iγ are important in linking integrin signaling to FAK activation.
|
|
|
|
|
|
|
