Among the 518 protein kinases encoded by the human kinome, several of them act as oncoproteins in human cancers. Like other eukaryotic genes, oncogenes encoding protein kinases are frequently subjected to alternative splicing in coding as well as noncoding sequences. In the present paper, we will illustrate how alternative splicing can significantly impact on the physiological functions of oncogenic protein kinases, as demonstrated by mouse genetic model studies. This includes examples of membrane-bound tyrosine kinases receptors (FGFR2, Ret, TrkB, ErbB4, and VEGFR) as well as cytosolic protein kinases (B-Raf). We will further discuss how regular alternative splicing events of these kinases are in some instances implicated in oncogenic processes during tumor progression (FGFR, TrkB, ErbB2, Abl, and AuroraA). Finally, we will present typical examples of aberrant splicing responsible for the deregulation of oncogenic kinases activity in cancers (AuroraB, Jak2, Kit, Met, and Ron). 1. Introduction The process of alternative splicing increases the complexity of the proteome encoded by higher eukaryotic genomes through the synthesis of different products from a single gene. Genes encoding for protein kinases do not escape this rule. While the whole human genome sequencing revealed 518 protein kinases encoding genes [1], a recent bioinformatics survey identified a larger repertoire of about 918 putative protein kinases represented mainly by splice variants from these 518 human genes [2]. This retrospectively gives credit to Tony Hunter’s previous witty estimate of “A thousand and one protein kinases” [3]. Protein kinases are among the largest families of genes in eukaryotes, representing approximately 1.7% of all human genes [1]. They are implicated in most of the essential cellular functions, and their deregulation often leads to pathological disorders, including cancer. Alteration of the expression and/or the activity of a number of protein kinases by point mutations, chromosomal translocations, or epigenetic mechanisms can directly initiate or contribute to the development of tumors. The first example came from the seminal discovery of the existence of cellular oncogenes, when the tyrosine kinase c-Src was identified thanks to its retroviral counterpart in the Rous Sarcoma Virus [4]. Since then, numerous oncogenic protein kinases have been discovered, among which EGFR, Abl, Kit, and B-Raf represent typical examples of success in the development of targeted drug therapy [5–7]. While in most cases constitutive activation of the protein catalytic activity is
References
[1]
G. Manning, D. B. Whyte, R. Martinez, T. Hunter, and S. Sudarsanam, “The protein kinase complement of the human genome,” Science, vol. 298, no. 5600, pp. 1912–1934, 2002.
[2]
K. Anamika, N. Garnier, and N. Srinivasan, “Functional diversity of human protein kinase splice variants marks significant expansion of human kinome,” BMC Genomics, vol. 10, article 622, 2009.
[3]
T. Hunter, “A thousand and one protein kinases,” Cell, vol. 50, no. 6, pp. 823–829, 1987.
[4]
D. Stehelin, H. E. Varmus, J. M. Bishop, and P. K. Vogt, “DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA,” Nature, vol. 260, no. 5547, pp. 170–173, 1976.
[5]
J. Zhang, P. L. Yang, and N. S. Gray, “Targeting cancer with small molecule kinase inhibitors,” Nature Reviews Cancer, vol. 9, no. 1, pp. 28–39, 2009.
[6]
K. T. Flaherty, F. S. Hodi, and B. C. Bastian, “Mutation-driven drug development in melanoma,” Current Opinion in Oncology, vol. 22, no. 3, pp. 178–183, 2010.
[7]
I. Vivanco and I. K. Mellinghoff, “Epidermal growth factor receptor inhibitors in oncology,” Current Opinion in Oncology, vol. 22, no. 6, pp. 573–578, 2010.
[8]
C. Ghigna, C. Valacca, and G. Biamonti, “Alternative splicing and tumor progression,” Current Genomics, vol. 9, no. 8, pp. 556–570, 2008.
[9]
M. Toutant, A. Costa, J. M. Studler, G. Kadaré, M. Carnaud, and J. A. Girault, “Alternative splicing controls the mechanisms of FAK autophosphorylation,” Molecular and Cellular Biology, vol. 22, no. 22, pp. 7731–7743, 2002.
[10]
C. Papin, A. Denouel-Galy, D. Laugier, G. Calothy, and A. Eychène, “Modulation of kinase activity and oncogenic properties by alternative splicing reveals a novel regulatory mechanism for B-Raf,” Journal of Biological Chemistry, vol. 273, no. 38, pp. 24939–24947, 1998.
[11]
I. Hmitou, S. Druillennec, A. Valluet, C. Peyssonnaux, and A. Eychène, “Differential regulation of B-Raf isoforms by phosphorylation and autoinhibitory mechanisms,” Molecular and Cellular Biology, vol. 27, no. 1, pp. 31–43, 2007.
[12]
C. Peyssonnaux and A. Eychène, “The Raf/MEK/ERK pathway: new concepts of activation,” Biology of the Cell, vol. 93, no. 1-2, pp. 53–62, 2001.
[13]
C. Brignatz, M. P. Paronetto, S. Opi et al., “Alternative splicing modulates autoinhibition and SH3 accessibility in the Src kinase Fyn,” Molecular and Cellular Biology, vol. 29, no. 24, pp. 6438–6448, 2009.
[14]
M. Rossel, A. Pasini, S. Chappuis et al., “Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations,” Oncogene, vol. 14, no. 3, pp. 265–275, 1997.
[15]
M. J. Lorenzo, G. D. Gish, C. Houghton et al., “RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2,” Oncogene, vol. 14, no. 7, pp. 763–771, 1997.
[16]
Y. Ishiguro, T. Iwashita, H. Murakami et al., “The role of amino acids surrounding tyrosine 1062 in ret in specific binding of the Shc phosphotyrosine-binding domain,” Endocrinology, vol. 140, no. 9, pp. 3992–3998, 1999.
[17]
R. P. Scott, S. Eketj？ll, H. Aineskog, and C. F. Ibá？ez, “Distinct turnover of alternatively spliced isoforms of the RET kinase receptor mediated by differential recruitment of the Cbl ubiquitin ligase,” Journal of Biological Chemistry, vol. 280, no. 14, pp. 13442–13449, 2005.
[18]
K. Elenius, C. J. Choi, S. Paul, E. Santiestevan, E. Nishi, and M. Klagsbrun, “Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase,” Oncogene, vol. 18, no. 16, pp. 2607–2615, 1999.
[19]
M. Sundvall, A. Korhonen, I. Paatero et al., “Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 11, pp. 4162–4167, 2008.
[20]
K. Elenius, G. Corfas, S. Paul et al., “A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester,” Journal of Biological Chemistry, vol. 272, no. 42, pp. 26761–26768, 1997.
[21]
X. Zhang, O. A. Ibrahimi, S. K. Olsen, H. Umemori, M. Mohammadi, and D. M. Ornitz, “Receptor specificity of the fibroblast growth factor family: the complete mammalian FGF family,” Journal of Biological Chemistry, vol. 281, no. 23, pp. 15694–15700, 2006.
[22]
V. P. Eswarakumar, I. Lax, and J. Schlessinger, “Cellular signaling by fibroblast growth factor receptors,” Cytokine and Growth Factor Reviews, vol. 16, no. 2, pp. 139–149, 2005.
[23]
T. Yokoyama, K. Takano, A. Yoshida et al., “DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation,” Journal of Cell Biology, vol. 177, no. 5, pp. 781–793, 2007.
[24]
J. Rauch, K. Moran-Jones, V. Albrecht, et al., “c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway,” Cancer Research, vol. 71, no. 13, pp. 4664–4674, 2011.
[25]
E. J. Huang and L. F. Reichardt, “Trk receptors: roles in neuronal signal transduction,” Annual Review of Biochemistry, vol. 72, pp. 609–642, 2003.
[26]
K. Luberg, J. Wong, C. S. Weickert, and T. Timmusk, “Human TrkB gene: novel alternative transcripts, protein isoforms and expression pattern in the prefrontal cerebral cortex during postnatal development,” Journal of Neurochemistry, vol. 113, no. 4, pp. 952–964, 2010.
[27]
G. T. Baxter, M. J. Radeke, R. C. Kuo et al., “Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2,” Journal of Neuroscience, vol. 17, no. 8, pp. 2683–2690, 1997.
[28]
C. R. Rose, R. Blum, B. Pichler, A. Lepier, K. W. Kafitz, and A. Konnerth, “Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells,” Nature, vol. 426, no. 6962, pp. 74–78, 2003.
[29]
K. Ohira, H. Kumanogoh, Y. Sahara et al., “A truncated tropo-myosine-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor,” Journal of Neuroscience, vol. 25, no. 6, pp. 1343–1353, 2005.
[30]
L. M. Ellis and D. J. Hicklin, “VEGF-targeted therapy: mechanisms of anti-tumour activity,” Nature Reviews Cancer, vol. 8, no. 8, pp. 579–591, 2008.
[31]
M. Lohela, M. Bry, T. Tammela, and K. Alitalo, “VEGFs and receptors involved in angiogenesis versus lymphangiogenesis,” Current Opinion in Cell Biology, vol. 21, no. 2, pp. 154–165, 2009.
[32]
R. L. Kendall and K. A. Thomas, “Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 22, pp. 10705–10709, 1993.
[33]
R. J. C. Albuquerque, T. Hayashi, W. G. Cho et al., “Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth,” Nature Medicine, vol. 15, no. 9, pp. 1023–1030, 2009.
[34]
J. M. L. Ebos, G. Bocci, S. Man et al., “A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma,” Molecular Cancer Research, vol. 2, no. 6, pp. 315–326, 2004.
[35]
L. De Moerlooze, B. Spencer-Dene, J. M. Revest, M. Hajihosseini, I. Rosewell, and C. Dickson, “An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis,” Development, vol. 127, no. 3, pp. 483–492, 2000.
[36]
V. P. Eswarakumar, E. Monsonego-Ornan, M. Pines, I. Antonopoulou, G. M. Morriss-Kay, and P. Lonai, “The IIIc alternative of Fgfr2 is a positive regulator of bone formation,” Development, vol. 129, no. 16, pp. 3783–3793, 2002.
[37]
J. M. Revest, B. Spencer-Dene, K. Kerr, L. De Moerlooze, I. Rosewell, and C. Dickson, “Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4,” Developmental Biology, vol. 231, no. 1, pp. 47–62, 2001.
[38]
M. K. Hajihosseini, S. Wilson, L. De Moerlooze, and C. Dickson, “A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffersyndrome-like phenotypes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 7, pp. 3855–3860, 2001.
[39]
E. De Graaff, S. Srinivas, C. Kilkenny et al., “Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis,” Genes and Development, vol. 15, no. 18, pp. 2433–2444, 2001.
[40]
A. Wong, S. Bogni, P. Kotka et al., “Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform,” Molecular and Cellular Biology, vol. 25, no. 21, pp. 9661–9673, 2005.
[41]
S. J. Fuller, K. Sivarajah, and P. H. Sugden, “ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium,” Journal of Molecular and Cellular Cardiology, vol. 44, no. 5, pp. 831–854, 2008.
[42]
R. S. Muraoka-Cook, M. A. Sandahl, K. E. Strunk et al., “ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo,” Molecular and Cellular Biology, vol. 29, no. 18, pp. 4935–4948, 2009.
[43]
J. B. Kearney, N. C. Kappas, C. Ellerstrom, F. W. DiPaola, and V. L. Bautch, “The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis,” Blood, vol. 103, no. 12, pp. 4527–4535, 2004.
[44]
B. K. Ambati, M. Nozaki, N. Singh et al., “Corneal avascularity is due to soluble VEGF receptor-1,” Nature, vol. 443, no. 7114, pp. 993–997, 2006.
[45]
T. Saarelainen, R. Pussinen, E. Koponen et al., “Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons have impaired long-term spatial memory but normal hippocampal LTP,” Synapse, vol. 38, no. 1, pp. 102–104, 2000.
[46]
T. Saarelainen, J. A. Lukkarinen, S. Koponen et al., “Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons show increased susceptibility to cortical injury after focal cerebral ischemia,” Molecular and Cellular Neurosciences, vol. 16, no. 2, pp. 87–96, 2000.
[47]
M. Korte, P. Carroll, E. Wolf, G. Brem, H. Thoenen, and T. Bonhoeffer, “Hippocampal long-term potentiation is impaired in mice lacking brain- derived neurotrophic factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 19, pp. 8856–8860, 1995.
[48]
S. G. Dorsey, C. L. Renn, L. Carim-Todd et al., “In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model,” Neuron, vol. 51, no. 1, pp. 21–28, 2006.
[49]
L. Carim-Todd, K. G. Bath, G. Fulgenzi et al., “Endogenous truncated TrkB.T1 receptor regulates neuronal complexity and TrkB kinase receptor function in vivo,” Journal of Neuroscience, vol. 29, no. 3, pp. 678–685, 2009.
[50]
J. V. Barnier, C. Papin, A. Eychene, O. Lecoq, and G. Calothy, “The mouse B-raf gene encodes multiple protein isoforms with tissue- specific expression,” Journal of Biological Chemistry, vol. 270, no. 40, pp. 23381–23389, 1995.
[51]
A. Eychene, I. Dusanter-Fourt, J. V. Barnier et al., “Expression and activation of B-raf kinase isoforms in human and murine leukemia cell lines,” Oncogene, vol. 10, no. 6, pp. 1159–1165, 1995.
[52]
A. Valluet, I. Hmitou, S. Davis, et al., “B-raf alternative splicing is dispensable for development but required for learning and memory associated with the hippocampus in the adult mouse,” PLoS ONE, vol. 5, no. 12, article e15272, 2010.
[53]
G. Yan, Y. Fukabori, G. McBride, S. Nikolaropolous, and W. L. McKeehan, “Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy,” Molecular and Cellular Biology, vol. 13, no. 8, pp. 4513–4522, 1993.
[54]
A. B. Moffa, S. L. Tannheimer, and S. P. Ethier, “Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells,” Molecular Cancer Research, vol. 2, no. 11, pp. 643–652, 2004.
[55]
J. Y. Cha, Q. T. Lambert, G. W. Reuther, and C. J. Der, “Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis,” Molecular Cancer Research, vol. 6, no. 3, pp. 435–445, 2008.
[56]
H. Itoh, Y. Hattori, H. Sakamoto et al., “Preferential alternative splicing in cancer generates a K-sam messenger RNA with higher transforming activity,” Cancer Research, vol. 54, no. 12, pp. 3237–3241, 1994.
[57]
N. Turner and R. Grose, “Fibroblast growth factor signalling: from development to cancer,” Nature Reviews Cancer, vol. 10, no. 2, pp. 116–129, 2010.
[58]
D. E. Johnson, J. Lu, H. Chen, S. Werner, and L. T. Williams, “The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain,” Molecular and Cellular Biology, vol. 11, no. 9, pp. 4627–4634, 1991.
[59]
E. Shi, M. Kan, J. Xu, F. Wang, J. Hou, and W. L. McKeehan, “Control of fibroblast growth factor receptor kinase signal transduction by heterodimerization of combinatorial splice variants,” Molecular and Cellular Biology, vol. 13, no. 7, pp. 3907–3918, 1993.
[60]
F. Wang, M. Kan, G. Yan, J. Xu, and W. L. McKeehan, “Alternately spliced NH2-terminal immunoglobulin-like loop I in the ectodomain of the fibroblast growth factor (FGF) receptor 1 lowers affinity for both heparin and FGF-1,” Journal of Biological Chemistry, vol. 270, no. 17, pp. 10231–10235, 1995.
[61]
S. M. Vickers, Z. Q. Huang, L. MacMillan-Crow, J. S. Greendorfer, and J. A. Thompson, “Ligand activation of alternatively spliced fibroblast growth factor receptor-1 modulates pancreatic adenocarcinoma cell malignancy,” Journal of Gastrointestinal Surgery, vol. 6, no. 4, pp. 546–553, 2002.
[62]
Y. A. Luqmani, C. Mortimer, C. Yiangou et al., “Expression of 2 variant forms of fibroblast growth factor receptor 1 in human breast,” International Journal of Cancer, vol. 64, no. 4, pp. 274–279, 1995.
[63]
F. Yamaguchi, H. Saya, J. M. Bruner, and R. S. Morrison, “Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 2, pp. 484–488, 1994.
[64]
D. C. Tomlinson and M. A. Knowles, “Altered splicing of FGFR1 is associated with high tumor grade and stage and leads to increased sensitivity to FGF1 in bladder cancer,” The American Journal of Pathology, vol. 177, no. 5, pp. 2379–2386, 2010.
[65]
D. J. Slamon, G. M. Clark, S. G. Wong, W. J. Levin, A. Ullrich, and W. L. McGuire, “Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene,” Science, vol. 235, no. 4785, pp. 177–182, 1987.
[66]
K. Y. Kwong and M. C. Hung, “A novel splice variant of HER2 with increased transformation activity,” Molecular Carcinogenesis, vol. 23, no. 2, pp. 62–68, 1998.
[67]
T. P. J. Garrett, N. M. McKern, M. Lou et al., “The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors,” Molecular Cell, vol. 11, no. 2, pp. 495–505, 2003.
[68]
F. Castiglioni, E. Tagliabue, M. Campiglio, S. M. Pupa, A. Balsari, and S. Ménard, “Role of exon-16-deleted HER2 in breast carcinomas,” Endocrine-Related Cancer, vol. 13, no. 1, pp. 221–232, 2006.
[69]
L. Zhongkui, C. Zhe, L. J. Chiao et al., “TrkBT1 induces liver metastasis of pancreatic cancer cells by sequestering Rho GDP dissociation inhibitor and promoting RhoA activation,” Cancer Research, vol. 69, no. 19, pp. 7851–7859, 2009.
[70]
S. O. Shin, K. H. Lee, J. H. Kim et al., “Alternative splicing in 5′-untranslational region of STK-15 gene, encoding centrosome associated kinase, in breast cancer cell lines,” Experimental and Molecular Medicine, vol. 32, no. 4, pp. 193–196, 2000.
[71]
C. H. Lai, J. T. Tseng, Y. C. Lee et al., “Translational up-regulation of Aurora-A in EGFR-overexpressed cancer,” Journal of Cellular and Molecular Medicine, vol. 14, no. 6, pp. 1520–1531, 2010.
[72]
A. Sistayanarain, K. Tsuneyama, H. Zheng et al., “Expression of Aurora-B kinase and phosphorylated histone H3 in hepatocellular carcinoma,” Anticancer Research, vol. 26, no. 5, pp. 3585–3593, 2006.
[73]
T. S. Lee, W. Ma, X. Zhang et al., “BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations,” Molecular Cancer Therapeutics, vol. 7, no. 12, pp. 3834–3841, 2008.
[74]
J. Laudadio, M. W. N. Deininger, M. J. Mauro, B. J. Druker, and R. D. Press, “An intron-derived insertion/truncation mutation in the BCR-ABL kinase domain in chronic myeloid leukemia patients undergoing kinase inhibitor therapy,” Journal of Molecular Diagnostics, vol. 10, no. 2, pp. 177–180, 2008.
[75]
F. X. Gruber, H. Hjorth-Hansen, I. Mikkola, L. Stenke, and T. Johansen, “A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib,” Leukemia, vol. 20, no. 11, pp. 2057–2060, 2006.
[76]
D. W. Sherbenou, O. Hantschel, L. Turaga et al., “Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia,” Leukemia, vol. 22, no. 6, pp. 1184–1190, 2008.
[77]
J. S. Khorashad, D. Milojkovic, and A. G. Reid, “Variant isoforms of BCR-ABL1 in chronic myelogenous leukemia reflect alternative splicing of ABL1 in normal tissue,” Molecular Cancer Therapeutics, vol. 9, no. 7, p. 2152, 2010.
[78]
I. Santamaria, A. S. Pitiot, and M. Balbin, “ABL alternative splicing is quite frequent in normal population,” Molecular Cancer Therapeutics, vol. 9, no. 3, p. 772, 2010.
[79]
N. B. Quigley, D. C. Henley, and R. A. Hubbard, “ABL kinase domain pseudoexon insertion is not uncommon in BCR-ABL transcripts,” Journal of Molecular Diagnostics, vol. 10, no. 5, pp. 475–476, 2008.
[80]
K. J. Morgan and D. G. Gilliland, “A role for JAK2 mutations in myeloproliferative diseases,” Annual Review of Medicine, vol. 59, pp. 213–222, 2008.
[81]
E. J. Baxter, L. M. Scott, P. J. Campbell et al., “Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders,” The Lancet, vol. 365, no. 9464, pp. 1054–1061, 2005.
[82]
R. Kralovics, F. Passamonti, A. S. Buser et al., “A gain-of-function mutation of JAK2 in myeloproliferative disorders,” The New England Journal of Medicine, vol. 352, no. 17, pp. 1779–1790, 2005.
[83]
M. Wanlong, H. Kantarjian, X. Zhang et al., “Mutation profile of JAK2 transcripts in patients with chronic myeloproliferative neoplasias,” Journal of Molecular Diagnostics, vol. 11, no. 1, pp. 49–53, 2009.
[84]
W. Ma, H. Kantarjian, X. Zhang et al., “JAK2 exon 14 deletion in patients with chronic myeloproliferative neoplasms,” PLoS ONE, vol. 5, no. 8, article e12165, 2010.
[85]
P. S. Crosier, S. T. Ricciardi, L. R. Hall, M. R. Vitas, S. C. Clark, and K. E. Crosier, “Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia,” Blood, vol. 82, no. 4, pp. 1151–1158, 1993.
[86]
W. M. Zhu, W. F. Dong, and M. Minden, “Alternate splicing creates two forms of the human kit protein,” Leukemia and Lymphoma, vol. 12, no. 5-6, pp. 441–447, 1994.
[87]
C. L. Corless, L. McGreevey, A. Town et al., “KIT gene deletions at the intron 10-exon 11 boundary in GI stromal tumors,” Journal of Molecular Diagnostics, vol. 6, no. 4, pp. 366–370, 2004.
[88]
L. L. Chen, M. Sabripour, E. F. Wu, V. G. Prieto, G. N. Fuller, and M. L. Frazier, “A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors,” Oncogene, vol. 24, no. 26, pp. 4271–4280, 2005.
[89]
L. Schmidt, F. -M. Duh, F. Chen, et al., “Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas,” Nature Genetics, vol. 16, no. 1, pp. 68–73, 1997.
[90]
C. C. Lee and K. M. Yamada, “Identification of a novel type of alternative splicing of a tyrosine kinase receptor. Juxtamembrane deletion of the c-met protein kinase C serine phosphorylation regulatory site,” Journal of Biological Chemistry, vol. 269, no. 30, pp. 19457–19461, 1994.
[91]
P. C. Ma, R. Jagadeeswaran, S. Jagadeesh et al., “Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer,” Cancer Research, vol. 65, no. 4, pp. 1479–1488, 2005.
[92]
M. Kong-Beltran, S. Seshagiri, J. Zha et al., “Somatic mutations lead to an oncogenic deletion of Met in lung cancer,” Cancer Research, vol. 66, no. 1, pp. 283–289, 2006.
[93]
R. Onozato, T. Kosaka, H. Kuwano, Y. Sekido, Y. Yatabe, and T. Mitsudomi, “Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers,” Journal of Thoracic Oncology, vol. 4, no. 1, pp. 5–11, 2009.
[94]
Y. Asaoka, M. Tada, T. Ikenoue et al., “Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion,” Biochemical and Biophysical Research Communications, vol. 394, no. 4, pp. 1042–1046, 2010.
[95]
J. H. Lee, F. G. Chong, C. L. Chong, D. K. Myung, and G. F. V. Woude, “An alternatively spliced form of Met receptor is tumorigenic,” Experimental and Molecular Medicine, vol. 38, no. 5, pp. 565–573, 2006.
[96]
Y. Lu, H. P. Yao, and M. H. Wang, “Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets,” Cancer Letters, vol. 257, no. 2, pp. 157–164, 2007.
[97]
C. Collesi, M. M. Santoro, G. Gaudino, and P. M. Comoglio, “A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype,” Molecular and Cellular Biology, vol. 16, no. 10, pp. 5518–5526, 1996.
[98]
Y. Q. Zhou, C. He, Y. Q. Chen, D. Wang, and M. H. Wang, “Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential,” Oncogene, vol. 22, no. 2, pp. 186–197, 2003.
[99]
C. Ghigna, S. Giordano, H. Shen et al., “Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene,” Molecular Cell, vol. 20, no. 6, pp. 881–890, 2005.
[100]
C. Ghigna, M. De Toledo, S. Bonomi et al., “Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: therapeutic potential of bifunctional oligonucleotides and indole derivatives,” RNA Biology, vol. 7, no. 4, pp. 495–503, 2010.
[101]
M. H. Wang, A. L. Kurtz, and Y. Q. Chen, “Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells,” Carcinogenesis, vol. 21, no. 8, pp. 1507–1512, 2000.
[102]
Y. Q. Chen, Y. Q. Zhou, D. Angeloni, A. L. Kurtz, X. Z. Qiang, and M. H. Wang, “Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines,” Experimental Cell Research, vol. 261, no. 1, pp. 229–238, 2000.
[103]
J. P. Venables, “Aberrant and alternative splicing in cancer,” Cancer Research, vol. 64, no. 21, pp. 7647–7654, 2004.
[104]
J. P. Venables, “Unbalanced alternative splicing and its significance in cancer,” BioEssays, vol. 28, no. 4, pp. 378–386, 2006.
[105]
P. J. Gardina, T. A. Clark, B. Shimada, et al., “Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array,” BMC Genomics, vol. 7, article 325, 2006.
[106]
J. P. Venables, R. Klinck, A. Bramard et al., “Identification of alternative splicing markers for breast cancer,” Cancer Research, vol. 68, no. 22, pp. 9525–9531, 2008.
[107]
R. Klinck, A. Bramard, L. Inkel et al., “Multiple alternative splicing markers for ovarian cancer,” Cancer Research, vol. 68, no. 3, pp. 657–663, 2008.
[108]
H. C. Cheung, K. A. Baggerly, S. Tsavachidis, et al., “Global analysis of aberrant pre-mRNA splicing in glioblastoma using exon expression arrays,” BMC Genomics, vol. 9, article 216, 2008.
[109]
K. Thorsen, K. D. S？rensen, A. Brems-Eskildsen et al., “Alternative splicing in colon, bladder, and prostate cancer identified by exon array analysis,” Molecular and Cellular Proteomics, vol. 7, no. 7, pp. 1214–1224, 2008.
[110]
L. Xi, A. Feber, V. Gupta et al., “Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer,” Nucleic Acids Research, vol. 36, no. 20, pp. 6535–6547, 2008.
[111]
P. Prinos, D. Garneau, J.-F. Lucier, et al., “Alternative splicing of SYK regulates mitosis and cell survival,” Nature Structural and Molecular Biology, vol. 18, no. 6, pp. 673–679, 2011.
