Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor for pleiotrophin (PTN), a growth factor involved in embryonic brain development (1-3). In ALK-expressing cells, PTN induces phosphorylation of both ALK and the downstream effectors IRS-1, Shc, PLCγ, and PI3 kinase (1). ALK was originally discovered as a nucleophosmin (NPM)-ALK fusion protein produced by a translocation (4). Investigators have found that the NPM-ALK fusion protein is a constitutively active, oncogenic tyrosine kinase associated with anaplastic lymphoma (4). Research literature suggests that activation of PLCγ by NPM-ALK may be a crucial step for its mitogenic activity and involved in the pathogenesis of anaplastic lymphomas (5).A distinct ALK oncogenic fusion protein involving ALK and echinoderm microtubule-associated protein like 4 (EML4) has been described in the research literature from a non-small cell lung cancer (NSCLC) cell line, with corresponding fusion transcripts present in some cases of lung adenocarcinoma. The short, amino-terminal region of the microtubule-associated protein EML4 is fused to the kinase domain of ALK (6-8).
Background: YAP and TAZ (WWTR1) are transcriptional co-activators that play a central role in the Hippo Signaling pathway that regulates cell, tissue and organ growth. YAP and TAZ are structurally and functionally similar, but exhibit differential patterns of expression among cells and tissues that suggest partially non-redundant functions (1). YAP and TAZ are dynamically regulated in response to internal and external cellular signals. Under growth conditions, YAP and TAZ are translocated to the nucleus, where they interact with transcription factors (e.g., TEA domain proteins) that regulate the transcription of genes that control proliferation and cell survival (2). The subcellular localization of YAP and TAZ is dynamically regulated by a kinase cascade that regulates the phosphorylation status of key residues within YAP and TAZ. Phosphorylation of YAP and TAZ (e.g., Ser109, Ser127, Ser397 in YAP; Ser89 in TAZ) results in their cytoplasmic translocation, sequestration by 14-3-3 proteins, and recruitment of the β-TrCP (SCF) ubiquitin ligase complex (3,4). This complex ubiquitinates YAP and TAZ, triggering their proteolytic degradation in the proteasome, thereby altering the transcription of genes that control proliferation and cell survival (3-5).
Background: YAP and TAZ (WWTR1) are transcriptional co-activators that play a central role in the Hippo Signaling pathway that regulates cell, tissue and organ growth. Under growth conditions, YAP and TAZ are translocated to the nucleus, where they interact with DNA-binding transcription factors (e.g., Transcriptional Enhanced Activation Domain [TEAD] proteins) to regulate the expression of genes that control fundamental aspects of cell function, such as proliferation and cell survival (1). A number of genes have been experimentally confirmed as targets of transcriptional regulation by YAP and TAZ. These include the extracellular matrix proteins CTGF, CYR61, and integrin β2 (2-4), the inhibitor of apoptosis protein (IAP) survivin (5), the mechano-sensitive nuclear envelope protein Lamin B2 (6), and the oncogenic receptor tyrosine kinase Axl (7).
Background: The Src family of protein tyrosine kinases, which includes Src, Lyn, Fyn, Yes, Lck, Blk, and Hck, are important in the regulation of growth and differentiation of eukaryotic cells (1). Src activity is regulated by tyrosine phosphorylation at two sites, but with opposing effects. While phosphorylation at Tyr416 in the activation loop of the kinase domain upregulates enzyme activity, phosphorylation at Tyr527 in the carboxy-terminal tail by Csk renders the enzyme less active (2).
Background: Members of the Janus family of tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2) are activated by ligands binding to a number of associated cytokine receptors (1). Upon cytokine receptor activation, Jak proteins become autophosphorylated and phosphorylate their associated receptors to provide multiple binding sites for signaling proteins. These associated signaling proteins, such as Stats (2), Shc (3), insulin receptor substrates (4), and focal adhesion kinase (FAK) (5), typically contain SH2 or other phosphotyrosine-binding domains.Activation of Jak kinases upon cytokine receptor binding is associated with tyrosine phosphorylation within their activation loops, including Tyr1034/1035 of Jak1, Tyr1007/1008 of Jak2, Tyr980/981 of Jak3, and Tyr1054/1055 of Tyk2. Many studies have indicated that various cytokine receptors have clear preferences that utilize distinct Jak family members. Aberrant regulation of Jak signaling is associated with a number of diseases, including myeloproliferative neoplasms, leukemia, and inflammatory disease (6).
Background: Protein phosphatase type 2A (PP2A) is an essential protein serine/threonine phosphatase that is conserved in all eukaryotes. PP2A is a key enzyme within various signal transduction pathways as it regulates fundamental cellular activities such as DNA replication, transcription, translation, metabolism, cell cycle progression, cell division, apoptosis and development (1-3). The core enzyme consists of catalytic C and regulatory A (or PR65) subunits, with each subunit represented by α and β isoforms (1). Additional regulatory subunits belong to four different families of unrelated proteins. Both the B (or PR55) and B' regulatory protein families contain α, β, γ and δ isoforms, with the B' family also including an ε protein. B'' family proteins include PR72, PR130, PR59 and PR48 isoforms, while striatin (PR110) and SG2NA (PR93) are both members of the B''' regulatory protein family. These B subunits competitively bind to a shared binding site on the core A subunit (1). This variable array of holoenzyme components, particularly regulatory B subunits, allows PP2A to act in a diverse set of functions. PP2A function is regulated by expression, localization, holoenzyme composition and post-translational modification. Phosphorylation of PP2A at Tyr307 by Src occurs in response to EGF or insulin and results in a substantial reduction of PP2A activity (4). Reversible methylation on the carboxyl group of Leu309 of PP2A has been observed (5,6). Methylation alters the conformation of PP2A, as well as its localization and association with B regulatory subunits (6-8).