Tyrosine kinases play a significant role in different cellular processes such as cell growth, apoptosis, and migration (Ingley 2012; Manning et al. 2002). Also tyrosine kinases regulate many inflammatory modulators that regulate immune response (Ingley 2012; Manning et al. 2002). Src family kinases (SFKs) include different tyrosine kinases like Src, Lyn, Yes, Fyn, Blk, Yrk, Fgr, Hck, and Lck. These intracellular membrane-associated non-receptor tyrosine kinases control different biological processes (Ingley et al. 2007; Parsons and Parsons 2004). The overexpression and higher activity of SFKs enhance different types of cancer cell growth, and various studies demonstrated the involvement of SFKs in various tumor progression and metastasis (Resh 1999; Boggon and Eck 2004; Selvakumar et al. 2007). Lyn is a member of the SFK family; solid tumors including colon cancer, prostate cancer, glioblastoma, and breast cancer exhibit higher Lyn expression (Sun et al. 1998, 2002). Various reports provide the evidence on the role of Lyn in the cancer progression and to consider Lyn as a therapeutic target in preventing solid tumor progression and metastasis (Resh 1999; Boggon and Eck 2004; Selvakumar et al. 2007).
Structure of Lyn
The structure of Lyn contains an N-terminal region encoding a myristoylation site and may contain a palmitoylation site, protein interaction domains (SH3 and SH2), and a kinase domain (SH1) (Boggon and Eck 2004). Lyn exists in two splice variants, designated as Lyn-A (p56) and Lyn-B (p53) isoforms, differed in the SH4 domain (Hibbs et al. 1995; Yi et al. 1991). The reversible N-terminal lipid modification (palmitoylation) and isoform-specific pY32 motif potentially complicate understanding Lyn’s function through their latent ability to regulate activity, interactions, and subcellular localization.
Lyn is regulated by protein interactions through its SH2/SH3 domains as well as via phosphorylation status (Koch et al. 1991). In its inactive state, Lyn is phosphorylated at its carboxyl terminus by C-terminal Src kinase (Csk) creating a binding site for its own SH2 domain. Lyn’s SH3 domain can bind an intramolecular proline motif situated between the SH2 and kinase domains (hinge region), helping generate a stabilized inactive kinase confirmation. Activation of Lyn involves dephosphorylation of the C-terminal tyrosine (Y508) by phosphatases such as CD45 (Wang et al. 2002) and SHP-2 (Futami et al. 2011), as well as through interactions with SH2 and/or SH3 domain-binding motifs, which compete with Lyn’s own SH3/SH2 intramolecular interaction sites, thus releasing the auto-inhibitory configuration of the kinase domain.
Lyn was expressed in 14% of various types of breast cancer. Lyn was expressed at higher levels in the invasive, mesenchymal breast cancer lines and higher levels in basal-like breast cancer lines (Choi et al. 2010; Finn et al. 2007; Huang et al. 2007). Knockdown of Lyn in mesenchymal breast cancer lines inhibited invasion. Further, knockdown of Lyn also led to reduced vimentin and N-cadherin and EMT markers but not increased E-cadherin, suggesting that Lyn directs only a portion of the mesenchymal phenotype. It has been reported that Lyn is a mediator of invasion and a possible new therapeutic target to clinically aggressive basal-like breast cancer (Choi et al. 2010).
Lyn was reported to be highly expressed in various types of breast cancer; specifically, Lyn is highly active in the invasive, mesenchymal phenotype and basal-like breast cancer (Choi et al. 2010; Finn et al. 2007; Huang et al. 2007). Lyn silencing led to downregulation of EMT markers such as vimentin and N-cadherin and alteration of mesenchymal phenotype. It has been reported that Lyn is a mediator of invasion and a possible new therapeutic target to clinically aggressive breast cancer (Choi et al. 2010). Recent studies reported Lyn is significantly highly expressed in triple-negative breast cancer (TNBC) cell lines; Lyn knockdown significantly inhibited the TNBC cell migration (Pénzes et al. 2014). Reduced Lyn levels alter claudin-2 expression; bafetinib (INNO-406), a Lyn-selective kinase inhibitor, decreases claudin-2 expression and reduces breast cancer liver metastasis (Tabariès et al. 2015). Knockdown of Lyn and the migration-related CRK-associated substrate (p130Cas) had a significant inhibitory effect on cell migration. The overexpression of mutated Lyn inhibits the anticancer activity of estrogen receptor (Schwarz et al. 2014). Lyn mediates the oncogenic effect of EGFR, the EGFR phosphorylated Lyn (Y32) phosphorylates MCM7, and that regulates DNA replication in breast cancer (Huang et al. 2013). SgK269 is a Lyn substrate, and downregulation of SgK269 in basal breast cancer cells enhanced the conversion of epithelial characteristics from mesenchymal phenotype (Croucher et al. 2013). All these studies point toward the role of Lyn in inducing the invasion of different types of breast cancer.
Lyn activation is considered as one of the cellular signaling that influences poor survival rate of lung cancer. In most lung cancer patients, EGFR is constitutively activated. Phosphorylated nuclear translocated EGFR is considered as a key coactivator of different cancer-inducing genes. Downregulation of Lyn inhibited the phosphorylation, nuclear translocation, and tumor-promoting activity of EGFR. The Lyn activation in lung cancer is mediated through PKCßII. The activated Lyn phosphorylates EGFR in association with RACK1 and Cbp/PAG proteins (Sutton et al. 2013). Also enhanced Lyn activity has significant influence on EGFR activation in cetuximab resistance model cells (Lida et al. 2013).
In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and invasion and metastasis (Park et al. 2008). Lyn expression and activity play a major role in the progression of prostate cancer and development. Lyn stabilizes and enhances the transcriptional activity of androgen receptor in prostate cancer (Zardan et al. 2014). Also Lyn overexpression enhanced AR transcriptional activity both in vitro and in vivo and accelerated castrate-resistant prostate cancer (CRPC) (Zardan et al. 2014). miR-3607 directly represses oncogenic Src family kinases Lyn and Src in prostate cancer (Saini et al. 2014).
In primary glioblastomas, Lyn was found to be the predominant active SFK, compared to normal brain or other types of brain tumors (Stettner et al. 2005). Same like other cancers, Lyn kinase activity is significantly elevated in glioblastoma tumors, and its activity promotes the glioblastoma malignant phenotype (Stettner et al. 2005). Lyn enhances the survival of glioblastoma cells by promoting autophagy and proliferation as well as inhibiting cell death, and Lyn promotes the same effects in vivo in xenograft tumors (Liu et al. 2013). Lyn gene expression levels increase with primary glioma tumor grade and inversely correlate with patient survival. Lyn promotes PDGF-mediated migration of glioblastoma cells (Ding et al. 2003).
Colon cancer is among the leading causes of cancer death in worldwide. Several SFKs are elevated in colon cancer. CD44, an adhesion and antiapoptotic molecule, is overexpressed in colon cancer. Overexpression of dominant-active Lyn recapitulated chemoresistance via a pathway shown to involve activation of phosphoinositide 3-kinase and Akt (Bates et al. 2001).
In Ewing’s sarcoma, a poorly differentiated bone/soft tissue cancer is characterized as sharing a common translocation generating an EWS-ETS fusion; Lyn also appears as a potential therapeutic target (Guan et al. 2008). Downregulation of Lyn by RNAi or small molecule inhibitors significantly inhibited the growth and metastatic capacity of these Ewing’s sarcoma lines in vitro and in vivo. It also appeared that the EWS-ETS fusion, a transcription factor, upregulated Lyn gene expression (Guan et al. 2008).
Leukemia and Lymphomas
Lyn kinase plays a significant role in different types of leukemia such as chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), and lymphoma (Donato et al. 2003; Dong and Byrd 2016). A number of reports discovered that the Lyn kinase is a downstream molecule of BCR-Abl fusion protein and contributes significantly toward the action of BCR-Abl-induced leukemogenesis (Warmuth et al. 2003; Wilson et al. 2002). Also Lyn kinase phosphorylates and activates the action BCR-Abl (Meyn et al. 2006). It has been reported that a direct link between Lyn and BCR-Abl signaling pathways as Lyn phosphorylates the Y177 motif of BCR-Abl (Wu et al. 2008), resulting in recruitment of the adaptor Gab2, a principle activator of the PI-3 kinase pathway, both of which are essential for BCR-Abl oncogenesis (Pendergast et al. 1993). Lyn is also involved in other signaling pathways in CML cells, including through BCR-Abl activation of JAK2 that then activates Lyn by preventing SHP-1 from turning off Lyn activity (Samanta et al. 2009). Studies have also confirmed the common activation of Lyn in primary acute myeloid leukemia (AML) and its critical role in maintaining proliferation and antiapoptotic pathways in these cells (Dos Santos et al. 2008). Inhibition of Lyn kinase activity (using genetic and small molecule inhibitors) in AML cell lines substantially decreased cell growth (Roginskaya et al. 1999). Different signaling molecules involved in proliferation and differentiation are associated with Lyn such as mTOR (Dos Santos et al. 2008; Lriyama et al. 2016). These studies indicate that Lyn kinase can be considered as a novel target to AML treatment. Lyn kinase activity was elevated in CLL, B-cell acute lymphoblastic leukemia (B-ALL), and B-cell chronic lymphocytic leukemia (B-CLL) (Contri et al. 2005; Hu et al. 2004). Recent studies suggested reduction in Lyn kinase activity that resulted in a decrease in CLL burden (Nguyen et al. 2016). In B-non-Hodgkin’s lymphomas (B-NHLs), an oncogenic role for Lyn was identified. Lyn inhibitors prevented Lyn-induced phosphorylation of Csk-binding protein (Cbp)/phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) adaptor (Cbp/PAG), dissociated the signalosome from rafts, and eventually induced death (Tauzin et al. 2008). ETV6-Lyn fusion protein interacts with STAT5 and leads to the direct activation of STAT5 that initiates the induction of myeloproliferative neoplasm (Takeda et al. 2011).
Several studies revealed that tumor invasion and metastasis are the real drivers of cancer mortality. Inhibiting tumor cell invasion and metastasis may represent a distinct approach to control cancer. Lyn may be a potential target to control the various cancers. By designing potent pharmacological inhibitor(s), targeting Lyn may result in control tumor metastasis, thereby effectively managing several cancer types.
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