Cloning of FRK, a novel human intracellular SRC-like tyrosine kinaseencoding gene

Lee, James; Wang, Zhengyu; Luoh, Shiuh Ming; Wood, William I.; Scadden, David T.

doi:10.1016/0378-1119(94)90817-6

Cited by 56 publications

(33 citation statements)

References 16 publications

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“…In a screen for other protein kinases expressed in human breast cancer cell lines and tissues, 1 we identified the Rak tyrosine kinase, 2 simultaneously identified as FRK. 3 Rak is a member of a subfamily of Src-related tyrosine kinases that includes Sik, 4 Brk, 5 Gtk 6 and Bsk/Iyk. 7 The distinguishing features of this subfamily of kinases is that they are all expressed primarily in epithelial tissues and share greater identity within the group than to Src itself.…”

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confidence: 99%

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

Meyer

Chang

et al. 2003

Intl Journal of Cancer

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Rak is a 54 kDa protein tyrosine kinase originally isolated from breast cancer cells and expressed in epithelial cells. It resembles the protooncogene Src structurally but lacks an amino-terminal myristylation site and localizes to the nuclear and perinuclear regions of the cell. We report here that expression of Rak in 2 different breast cancer cell lines inhibits growth and causes G 1 arrest of the cell cycle. This growth inhibition is kinase-dependent but does not require the Rak SH2 or SH3 domain. Rak also binds to the pRb tumor-suppressor protein but inhibits growth even in cells that lack pRb. These results suggest that Rak regulates cell growth by phosphorylating perinuclear proteins and has a function that is distinct from the Src-related kinase family. Protein tyrosine kinases play key roles in signal transduction and influence a number of cellular processes that maintain the balance between proliferation, differentiation, senescence and apoptosis. Receptor tyrosine kinases such as HER2/neu and the EGFR are expressed in breast cancer and represent important therapeutic targets. In a screen for other protein kinases expressed in human breast cancer cell lines and tissues, 1 we identified the Rak tyrosine kinase, 2 simultaneously identified as FRK. 3 Rak is a member of a subfamily of Src-related tyrosine kinases that includes Sik, 4 Brk, 5 Gtk 6 and Bsk/Iyk. 7 The distinguishing features of this subfamily of kinases is that they are all expressed primarily in epithelial tissues and share greater identity within the group than to Src itself. The Rak-related kinases are distinct from CSK 8,9 subfamily because they contain a tyrosine near their carboxy termini.All Rak-related kinases contain SH2 and SH3 domains 10 at the amino termini and a kinase domain at the carboxy termini. SH2 domains bind to phosphorylated tyrosine residues, 11 whereas SH3 domains associate with proline-rich sequences of target proteins. 12 These domains are involved in both intermolecular associations that regulate signaling cascades and intramolecular associations that autoregulate protein kinase activity. [13][14][15] At its carboxy terminus, Rak has a kinase domain and associated autophosphorylation activity. 2 In addition, the carboxy-terminal tyrosine of Rak is phosphorylated in vitro by CSK, suggesting that this may be a regulatory site. 2 While Rak resembles Src structurally, it lacks the myristylation signal that localizes Src to the cell membrane. Instead, Rak contains a putative bipartite nuclear localization signal within its SH2 domain. Rak cofractionates with nuclear proteins in some cell lines 2 but is primarily perinuclear in others and was detected in the perinuclear region in the present study. Additionally, Rak associates with pRb during the G 1 and S phases of the cell cycle by interacting with the A/B pocket of pRb, and endogenous Rak is elevated during the G 1 phase of the cell cycle. 16 Nuclear localization has also been reported for the related murine Iyk. 17 Rak also contrasts with Src tyrosine kinase in its bi...

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confidence: 99%

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

Meyer

Chang

et al. 2003

Intl Journal of Cancer

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“…Mouse GTK is highly homologous to human FRK/RAK (13,14) and rat GTK (15). Little is known about the function of these tyrosine kinases, and they have been suggested to be members of a subgroup within the Src family with certain specific characteristics compared with the other Src family members.…”

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confidence: 99%

GTK, a Src-related Tyrosine Kinase, Induces Nerve Growth Factor-independent Neurite Outgrowth in PC12 Cells through Activation of the Rap1 Pathway

Annerén¹,

Reedquist²,

Bos³

et al. 2000

Journal of Biological Chemistry

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The rat pheochromocytoma cell line PC12 is extensively used as a model for studies of neuronal cell differentiation. These cells develop a sympathetic neuronlike phenotype when cultured in the presence of nerve growth factor. The present study was performed in order to assess the role of mouse GTK (previously named BSK/IYK), a cytoplasmic tyrosine kinase belonging to the Src family, for neurite outgrowth in PC12 cells. We report that PC12 cells stably overexpressing GTK exhibit a larger fraction of cells with neurites as compared with control cells, and this response is not accompanied by an increased ERK activity. Treatment of the cells with the MEK inhibitor PD98059 did not reduce the GTK-dependent increased in neurite outgrowth. GTK expression induces a nerve growth factor-independent Rap1 activation, probably through altered CrkII signaling. We observe increased CrkII complex formation with p130Cas , focal adhesion kinase (FAK), and Shb in PC12-GTK cells. The expression of GTK also correlates with a markedly increased content of FAK, phosphorylation of the adaptor protein Shb, and an association between these two proteins. Transient transfection of GTK-overexpressing cells with RalGDS-RBD or Rap1GAP, inhibitors of the Rap1 pathway, reduces the GTK-dependent neurite outgrowth. These data suggest that GTK participates in a signaling pathway, perhaps involving Shb, FAK and Rap1, that induces neurite outgrowth in PC12 cells.

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“…Rak/Frk, predicted to encode an 54 kDa protein consisting of 505 amino acids, was cloned from human breast cancer cells (Rak) (Cance et al 1994) and a human B cell lymphoma cell line (Frk) (Lee et al 1994). Although structurally resembling the Src family members, Rak/Frk lacks the myristoylation signal present in all the Src family PTKs, and its N-terminal region is significantly shorter than the N-terminal unique domains of the Src family members (Fig.…”

Section: Rak/frkmentioning

confidence: 99%

“…2). Overall it displays 50% amino acid identity to the Src family members c-Src, Lyn and Fyn, although the sequences surrounding the autophosphorylation site Tyr and the C-terminal Tyr differ sharply from them (Cance et al 1994;Lee et al 1994). Interestingly, its closest relative is a Hydra attenuata PTK termed STK (Cance et al 1994).…”

Section: Rak/frkmentioning

confidence: 99%

Vertebrate non‐receptor protein–tyrosine kinase families

1996

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Many non‐receptor protein–tyrosine kinases (PTKs) function as subunits of receptors, either receptors with or without intrinsic PTK catalytic activity of their own. There are currently at least 33 known vertebrate genes that encode non‐receptor PTKs. These can be divided into nine families: Abl, Fes/Fer, Syk/Zap70, Jak, Tec, Fak, Ack, Src, and Csk. Four additional non‐receptor PTKs (Rlk/Txk, Srm, Rak/Frk, and Brk/Sik) do not appear to belong to any of the defined families. Here we review current knowledge of the general roles of non‐receptor PTKs, as well as the characteristic features and functions of each family and its family members.

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Cloning of FRK, a novel human intracellular SRC-like tyrosine kinaseencoding gene

Cited by 56 publications

References 16 publications

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

Breast cancer cell line proliferation blocked by the Src‐related Rak tyrosine kinase

GTK, a Src-related Tyrosine Kinase, Induces Nerve Growth Factor-independent Neurite Outgrowth in PC12 Cells through Activation of the Rap1 Pathway

Vertebrate non‐receptor protein–tyrosine kinase families

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