The role of Src in solid tumors

Abstract

The proto-oncogene c-Src (Src) encodes a nonreceptor tyrosine kinase whose expression and activity are correlated with advanced malignancy and poor prognosis in a variety of human cancers. Nine additional enzymes with homology to Src have been identified and collectively are referred to as Src family kinases (SFKs). Together, SFKs represent the largest family of nonreceptor tyrosine kinases and interact directly with receptor tyrosine kinases, G-protein-coupled receptors, steroid receptors, signal transducers and activators of transcription, and molecules involved in cell adhesion and migration. These interactions lead to a diverse array of biological functions including proliferation, cell growth, differentiation, cell shape, motility, migration, angiogenesis, and survival. Studies investigating mutational activation of Src in human cancers suggest that this may be a rare event and that wild-type Src is weakly oncogenic. Thus, the role of Src in the development and progression of human cancer remains unclear. Recently, it was suggested that increased SFK protein levels and, more importantly, SFK tyrosine kinase activity are linked to cancer progression and metastatic disease by facilitating the action of other signaling proteins. This accumulating body of evidence indicates that SFKs may represent a promising therapeutic target for the treatment of solid tumors. This review discusses the role of SFKs in solid tumors and the recent therapeutic advances aimed at targeting this family of tyrosine kinases in cancer.

Figure 1

Comparison of the molecular structures of human c-Src, chicken c-Src, and chicken v-Src. All three proteins contain four Src homology (SH) domains and a unique amino-terminal domain of unknown function. The SH1 domain contains the kinase domain and a conserved tyrosine residue involved in autophosphorylation (Tyr419 in human c-SRC; Tyr416 in chicken). Chicken v-Src lacks the carboxy-terminal negative-regulatory domain and contains 12 substituted carboxy-terminal amino acids, as well as numerous point mutations throughout the molecule, explaining the high level of activity of this protein. *Reprinted with permission from Nat Rev Cancer 2004;4:470–480.

Figure 2

Activation of c-Src. The left panel represents the inactive conformation of Src in which Tyr527 (chicken c-Src) interacts with the SH2 domain, positioning the SH3 domain to interact with the linker between the SH2 and catalytic domains. The middle panel illustrates different mechanisms involved in the activation of Src, and the right panel represents the open or active conformation. *Reprinted with permission from Nat Rev Mol Cell Biol 2001;2:467–475.

Figure 3

Postulated regulation of c-Src by surface receptors. Src can be activated by several types of cell surface or cytoplasmic receptor. Shown here is, from left to right, a receptor tyrosine kinase such as the platelet-derived growth factor receptor; a G-protein-coupled receptor such as the β-adrenergic receptor; and an integrin bound to extracellular matrix. In each case, Src is activated by binding of a ligand to the SH2 and/or SH3 domains. In the case of a receptor tyrosine kinase, the SH2 ligand is a phosphotyrosine residue of the autophosphorylated receptor. In the case of the β-adrenergic receptor, the SH3 ligand is a proline motif of β-arrestin bound to the receptor. In the case of an integrin, the SH2 ligand is a phosphorylated tyrosine residue of autophosphorylated focal adhesion kinase (FAK). *Reprinted with permission from Nat Rev Mol Cell Biol 2001;2:467–475.

Figure 4

Selected examples of Src signal transduction pathways. CAS = Crk-associated substrate; ERK = extracellular signal-regulated kinase; FAK = focal adhesion kinase; IKK = IkB kinase; IL-8 = interleukin 8; JNK = Jun N-terminal kinase; MAPK = mitogen-activated protein kinase; MEK = mitogen-activated protein kinase kinase MAPK/ERK kinase; MLCK = myosin light chain kinase; NFKB = nuclear factor kB; PI3K = phosphatidylinositol 3-kinase; RhoGAP Rho GTPase-activating protein; RTK = receptor tyrosine kinase; SOS = son of sevenless; STAT3 = signal transducer and activator of transcription 3; VEGF = vascular endothelial growth factor. *Reprinted with permission from Summy et al. 2006.