Differential transformation capacity of Src family kinases during the initiation of prostate cancer

Abstract

Src family kinases (SFKs) are pleiotropic activators that are responsible for integrating signal transduction for multiple receptors that regulate cellular proliferation, invasion, and metastasis in a variety of human cancers. Independent groups have identified increased expression of individual SFK members during prostate cancer progression, raising the question of whether SFKs display functional equivalence. Here, we show that Src kinase, followed by Fyn kinase and then Lyn kinase, exhibit ranked tumorigenic potential during both paracrine-induced and cell-autonomousinitiated prostate cancer. This quantitative variation in transformation potential appears to be regulated in part by posttranslational palmitoylation. Our data indicate that development of inhibitors against specific SFK members could provide unique targeted therapeutic strategies.paracrine FGF10 signaling | tyrosine kinase | tissue regeneration S rc family kinases (SFKs) are a group of nonreceptor tyrosine kinases composed of nine highly homologous members with four conserved protein domains (1). All SFK members have an SH4 domain that mediates membrane association via myristoylation and, depending on the SFK, palmitoylation, as well as SH3 and SH2 domains that mediate inter-and intramolecular interactions, and finally the SH1 kinase domain (1). SFKs represent central convergence points for multiple receptors and cellautonomous signaling pathways that mediate enhanced cellular proliferation, cell migration, and metastatic potential in cancer progression (1, 2). Drug resistance and failure to efficiently inhibit SFKs have spurred the development of a new generation of SRC inhibitors that are currently in clinical trials. These drugs represent a prospectively efficacious therapeutic strategy against numerous solid malignancies and second-line treatment of leukemia (3). However, due to the high homology of SFK members and kinase domains conserved in numerous receptor tyrosine kinases, these inhibitors targeting Src kinase and BCR/ABL also inhibit other SFK members and/or several receptor tyrosine kinases (3). Off-target effects by these drugs can impair normal tissue function, leading to clinically adverse symptoms including diarrhea, rash, and cardiac toxicity (4, 5).Despite structural similarities, individual SFK members have specific cellular functions in normal development. Genetic knockout of Src, Lyn, or Fyn kinases in mice and derivative cells, respectively, exhibit defects in the development of bone, peripheral B cells, or T-cell receptor signaling (6-8). The specificity of individual SFK members may rely on their preferential association with cell surface receptors. For example, c-Src, but not Fyn or Lyn, is associated with α IIb β 3 integrin in blood platelet signal cascades (9). In contrast, Lyn and Fyn, but not Src, are preferentially recruited to the Fc receptor γ-chain and mediate platelet glycoprotein VI receptor signal transduction (10). In human glioblastoma cells, cooperation of integrin α v β 3 with platelet-derived growth factor ...

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

“…Our observation of SRC activity supports previous work that this kinase synergizes with other genes, including AR, to contribute to prostate adenocarcinoma (18,51). SRC has also been shown to interact with the intracellular region of ERBB2 (HER-2), supporting the notion that SRC may be an important node for targeted therapy in advanced prostate cancer (17,52).…”

Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

“…Recent in vivo studies have shown that LYN knockout or hyperactivation animal models provide compelling evidence that LYN cannot have possibility to initiate neoplasia. 20,29,51 However, accumulated evidence has indicated that LYN plays a role in tumor progression. 52,53 These investigations elucidated that LYN plays an oncogenic role in these tumors, and promotes the tumor progression.…”

Oncogene-mediated alterations in chromatin conformation

“…6 and includes FYN, a known prostate cancer oncogene with a role in cell invasion (27,28), and MOXD1, a gene up-regulated in primary compared with metastatic prostate cancer (29). These genes are bound by ERG proximally or distally (Fig.…”