Biomedical Engineering Reference
In-Depth Information
established forms the signalling network. In this i rst decade of the 21
st
century,
we now have an extensive (although not yet comprehensive) view of the signalling
networks that are established by integrin receptor stimulation. While there are
still important questions to be answered, we now have sui cient knowledge to
begin targeting adhesion signalling as a new approach to the treatment of cancer.
h is chapter describes current understanding of the phospho-regulation of the
adhesion proteins, focusing on FAK, Src, paxillin and p130Cas. We discuss the
antibodies that have been created to study the phosphorylation modii cations of
these proteins, approaches that are being employed to target these proteins in novel
anti-cancer therapies and the potential for these phospho-proteins as biomarkers
for chemotherapeutic activity.
INTRODUCTION
Hanahan and Weinberg (2000) described six essential changes to normal cellular
function that determine progression to malignancy: 'self-sui ciency in growth
signals, evasion of programmed cell death, limitless replicative potential, sustained
angiogenesis, and tissue invasion and metastasis. Transmembrane integrin
receptor interaction with the extracellular matrix (ECM) stimulates the activation
of phosphorylation-dependent signalling cascades that play a critical role in each
of these six hallmarks of cancer. Protein phosphorylation creates binding sites that
facilitates protein-protein interaction, thereby creating networks of interacting
proteins. Kinases catalyse the transfer of the γ-phosphoryl group of ATP to
serine, threonine or tyrosine amino acids in the recipient protein. Based on the
growing realization that kinases are essential regulators of adhesion-dependent
signalling in cancer, they—and their phosphorylated substrates—have become
important new targets for treating malignancies and for monitoring activity of
chemotherapeutic agents. h e following sections provide information regarding
the phospho-regulation of focal adhesion kinase (FAK), Src, paxillin and p130Cas
and discuss how studies of these proteins have led to novel anti-cancer therapies
and biomarkers for chemotherapy ei cacy.
ADHESION SIGNALLING AND CANCER
Integrin Receptors
h e integrin receptor family of proteins are the major receptors that mediate
cellular adhesion to the ECM. In mammals, 8 β- and 18 α-integrin subunits
heterodimerize to form at least 24 αβ receptors with both overlapping and distinct
specii cities for ECM components including i bronectin, laminin, i brinogen,
tenascin and collagen. h e repertoire of receptor expression is tissue and cell-type
specii c, is regulated during development and alters during cancer progression.
