The Grb-2 associated binder (Gab) family of scaffolding/adaptor/docking proteins is a group of three molecules with significant roles in cytokine receptor signaling. Gabs possess structural motifs for phosphorylation-dependent receptor recruitment, Grb2 binding, and activation of downstream signaling pathways through p85 and SHP-2. In addition, Gabs participate in hematopoiesis and regulation of immune response which can be aberrantly activated in cancer and inflammation. The multifunctionality of Gab adapters might suggest that they would be too difficult to consider as candidates for “targeted” therapy. However, the one drug/one target approach is giving way to the concept of one drug/multiple target approach since few cancers are addicted to a single signaling molecule for survival and combination drug therapies can be problematic. In this paper, we cover recent findings on Gab multi-functionality, binding partners, and their role in hematological malignancy and examine the concept of Gab-targeted therapy. 1. Discovery and Similarities of Gab Family Members The Gab proteins, Gab1, Gab2, and Gab3, comprise a family of scaffolding/docking molecules involved in multiple signaling pathways mediated by receptor tyrosine kinases (RTKs) and non-RTK receptors. Gab proteins integrate and amplify signals from a wide variety of sources including growth factor, cytokine, and antigen receptors, as well as cell adhesion molecules. They are subject to complex regulation by feedforward and feedback phosphorylation events as well as protein-protein interactions. Gab proteins range from 50 to 100？kDa in size [1] and were originally identified as the mammalian homologs of the daughter of sevenless (DOS) Drosophila adapter proteins [2, 3]. They also display sequence similarity to Suppressor of Clear 1 (Soc1), which was identified by genetic screen in C. elegans [3, 4]. Gab1 was originally identified as a binding protein for Grb-2 [5], and Gab2 was isolated by the purification of a binding partner for SHP [6]. The discovery of Gab3 was aided by a large sequencing project, and its isolation was based on sequence similarities to Gab1 and Gab2 [7]. Very recent entries at both the genomic DNA and transcript level have been recorded for Gab4 gene in both humans and chimpanzees, but this gene is not present in mice. The human Gab4 gene is located on chromosome 22q11.1 and its nucleotide sequence is most related to Gab2 [8]. The overall sequence homology between Gab family members is about 40–50%. All Gab proteins share a similar modular structure, including a Pleckstrin
References
[1]
H. Gu and B. G. Neel, “The “Gab” in signal transduction,” Trends in Cell Biology, vol. 13, no. 3, pp. 122–130, 2003.
[2]
T. Raabe, J. Riesgo-Escovar, X. Liu et al., “DOS, a novel pleckstrin homology domain-containing protein required for signal transduction between sevenless and Ras1 in drosophila,” Cell, vol. 85, no. 6, pp. 911–920, 1996.
[3]
R. Herbst, P. M. Carroll, J. D. Allard, J. Schilling, T. Raabe, and M. A. Simon, “Daughter of sevenless is a substrate of the phosphotyrosine phosphatase corkscrew and functions during sevenless signaling,” Cell, vol. 85, no. 6, pp. 899–909, 1996.
[4]
J. L. Schutzman, C. Z. Borland, J. C. Newman, M. K. Robinson, M. Kokel, and M. J. Stern, “The caenorhabditis elegans EGL-15 signaling pathway implicates a DOS-like multisubstrate adaptor protein in fibroblast growth factor signal transduction,” Molecular and Cellular Biology, vol. 21, no. 23, pp. 8104–8116, 2001.
[5]
M. Holgado-Madruga, D. R. Emlet, D. K. Moscatello, A. K. Godwin, and A. J. Wong, “A Grb2-associated docking protein in EGF- and insulin-receptor signalling,” Nature, vol. 379, no. 6565, pp. 560–564, 1996.
[6]
H. Gu, J. C. Pratt, S. J. Burakoff, and B. G. Neel, “Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation,” Molecular Cell, vol. 2, no. 6, pp. 729–740, 1998.
[7]
I. Wolf, B. J. Jenkins, Y. Liu et al., “Gab3, a new DOS/Gab family member, facilitates macrophage differentiation,” Molecular and Cellular Biology, vol. 22, no. 1, pp. 231–244, 2002.
[8]
F. U. Wohrle, R. J. Daly, and T. Brummer, “Function, regulation and pathological roles of the Gab/DOS docking proteins,” Cell Communication and Signaling, vol. 7, p. 22, 2009.
[9]
C. Zhao, D. H. Yu, R. Shen, and G. S. Feng, “Gab2, a new pleckstrin homology domain-containing adapter protein, acts to uncouple signaling from ERK kinase to Elk-1,” The Journal of Biological Chemistry, vol. 274, no. 28, pp. 19649–19654, 1999.
[10]
Y. Liu and L. R. Rohrschneider, “The gift of Gab,” Febs Letters, vol. 515, no. 1-3, pp. 1–7, 2002.
[11]
B. G. Neel, H. Gu, and L. Pao, “The “Shp”ing news: SH2 domain-containing tyrosine phosphatases in cell signaling,” Trends in Biochemical Sciences, vol. 28, no. 6, pp. 284–293, 2003.
[12]
D. Sakkab, M. Lewitzky, G. Posern et al., “Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL,” The Journal of Biological Chemistry, vol. 275, no. 15, pp. 10772–10778, 2000.
[13]
C. Boudot, Z. Kadri, E. Petitfrère et al., “Phosphatidylinositol 3-kinase regulates glycosylphosphatidylinositol hydrolysis through PLC-γ2 activation in erythropoietin-stimulated cells,” Cellular Signalling, vol. 14, no. 10, pp. 869–878, 2002.
[14]
T. D. Lamkin, S. F. Walk, L. Liu, J. E. Damen, G. Krystal, and K. S. Ravichandran, “Shc interaction with Shc homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP,” The Journal of Biological Chemistry, vol. 272, no. 16, pp. 10396–10401, 1997.
[15]
H. Chin, T. Saito, A. Arai et al., “Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells,” Biochemical and Biophysical Research Communications, vol. 239, no. 2, pp. 412–417, 1997.
[16]
S. Ni, C. Zhao, G. S. Feng, R. F. Paulson, and P. H. Correll, “A novel stat3 binding motif in Gab2 mediates transformation of primary hematopoietic cells by the Stk/Ron receptor tyrosine kinase in response to friend virus infection,” Molecular and Cellular Biology, vol. 27, no. 10, pp. 3708–3715, 2007.
[17]
N. Harir, C. Pecquet, M. Kerenyi et al., “Constitutive activation of stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias,” Blood, vol. 109, no. 4, pp. 1678–1686, 2007.
[18]
C. Crouin, M. Arnaud, F. Gesbert, J. Camonis, and J. Bertoglio, “A yeast two-hybrid study of human p97/Gab2 interactions with its SH2 domain-containing binding partners,” Febs Letters, vol. 495, no. 3, pp. 148–153, 2001.
[19]
M. Arnaud, C. Crouin, C. Deon, D. Loyaux, and J. Bertoglio, “Phosphorylation of Grb2-associated binder 2 on serine 623 by ERK MAPK regulates its association with the phosphatase SHP-2 and decreases STAT5 activation,” Journal of Immunology, vol. 173, no. 6, pp. 3962–3971, 2004.
[20]
D. K. Lynch and R. J. Daly, “PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2,” The Embo Journal, vol. 21, no. 1-2, pp. 72–82, 2002.
[21]
S. Zhang and H. E. Broxmeyer, “Flt3 ligand induces tyrosine phosphorylation of Gab1 and Gab2 and their association with Shp-2, Grb2, and PI3 kinase,” Biochemical and Biophysical Research Communications, vol. 277, no. 1, pp. 195–199, 2000.
[22]
C. Bourgin, R. P. Bourette, S. Arnaud, Y. Liu, L. R. Rohrschneider, and G. Mouchiroud, “Induced expression and association of the Mona/Gads adapter and Gab3 scaffolding protein during monocyte/macrophage differentiation,” Molecular and Cellular Biology, vol. 22, no. 11, pp. 3744–3756, 2002.
[23]
K. Carlberg and L. R. Rohrschneider, “Characterization of a novel tyrosine phosphorylated 100-kDa protein that binds to SHP-2 and phosphatidylinositol 3'-kinase in myeloid cells,” Journal of Biological Chemistry, vol. 272, no. 25, pp. 15943–15950, 1997.
[24]
A. W. Lee and D. J. States, “Both src-dependent and—independent mechanisms mediate phosphatidylinositol 3-kinase regulation of colony-stimulating factor 1-activated mitogen-activated protein kinases in myeloid progenitors,” Molecular and Cellular Biology, vol. 20, no. 18, pp. 6779–6798, 2000.
[25]
Y. Liu, B. Jenkins, Jun Lim Shin, and L. R. Rohrschneider, “Scaffolding protein Gab2 mediates differentiation signaling downstream of Fms receptor tyrosine kinase,” Molecular and Cellular Biology, vol. 21, no. 9, pp. 3047–3056, 2001.
[26]
P. D. Simoncic, A. Bourdeau, A. Lee-Loy et al., “T-cell protein tyrosine phosphatase (Tcptp) is a negative regulator of colony-stimulating factor 1 signaling and macrophage differentiation,” Molecular and Cellular Biology, vol. 26, no. 11, pp. 4149–4160, 2006.
[27]
K. Nishida, L. Wang, E. Morii et al., “Requirement of Gab2 for mast cell development and KitL/c-Kit signaling,” Blood, vol. 99, no. 5, pp. 1866–1869, 2002.
[28]
M. Yu, J. Luo, W. Yang et al., “The scaffolding adapter Gab2, via Shp-2, regulates Kit-evoked mast cell proliferation by activating the Rac/JNK pathway,” The Journal of Biological Chemistry, vol. 281, no. 39, pp. 28615–28626, 2006.
[29]
K. Nishida, Y. Yoshida, M. Itoh et al., “Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T-and B-cell antigen receptors,” Blood, vol. 93, no. 6, pp. 1809–1816, 1999.
[30]
S. Takaki, H. Morita, Y. Tezuka, and K. Takatsu, “Enhanced hematopoiesis by hematopoietic progenitor cells lacking intracellular adaptor protein, Lnk,” The Journal of Experimental Medicine, vol. 195, no. 2, pp. 151–160, 2002.
[31]
A. K. Gandhi, J. Kang, S. Naziruddin, A. Parton, P. H. Schafer, and D. I. Stirling, “Lenalidomide inhibits proliferation of namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly,” Leukemia Research, vol. 30, no. 7, pp. 849–858, 2006.
[32]
K. Nishigaki, C. Hanson, T. Ohashi, D. Thompson, K. Muszynski, and S. Ruscetti, “Erythroid cells rendered erythropoietin independent by infection with friend spleen focus-forming virus show constitutive activation of phosphatidylinositol 3-kinase and Akt kinase: involvement of insulin receptor substrate-related adapter proteins,” Journal of Virology, vol. 74, no. 7, pp. 3037–3045, 2000.
[33]
E. van den Akker, T. van Dijk, M. Parren-Van Amelsvoort et al., “Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors,” Blood, vol. 103, no. 12, pp. 4457–4465, 2004.
[34]
D. Bouscary, F. Pene, Y. E. Claessens et al., “Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation,” Blood, vol. 101, no. 9, pp. 3436–3443, 2003.
[35]
Q. S. Zhu, L. J. Robinson, V. Roginskaya, and S. J. Corey, “G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses,” Blood, vol. 103, no. 9, pp. 3305–3312, 2004.
[36]
H. Gu, H. Maeda, J. J. Moon et al., “New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway,” Molecular and Cellular Biology, vol. 20, no. 19, pp. 7109–7120, 2000.
[37]
H. Gu, J. D. Griffin, and B. G. Neel, “Characterization of two SHP-2-associated binding proteins and potential substrates in hematopoietic cells,” The Journal of Biological Chemistry, vol. 272, no. 26, pp. 16421–16430, 1997.
[38]
C. Lecoq-Lafon, F. Verdier, S. Fichelson et al., “Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase,” Blood, vol. 93, no. 8, pp. 2578–2585, 1999.
[39]
M. Takahashi-Tezuka, Y. Yoshida, T. Fukada et al., “Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase,” Molecular and Cellular Biology, vol. 18, no. 7, pp. 4109–4117, 1998.
[40]
K. Podar, G. Mostoslavsky, M. Sattler et al., “Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells,” The Journal of Biological Chemistry, vol. 279, no. 20, pp. 21658–21665, 2004.
[41]
A. Badache and N. E. Hynes, “Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells,” Cancer Research, vol. 61, no. 1, pp. 383–391, 2001.
[42]
T. Fukada, M. Hibi, Y. Yamanaka et al., “Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis,” Immunity, vol. 5, no. 5, pp. 449–460, 1996.
[43]
Y. Nakaoka, K. Nishida, Y. Fujio et al., “Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes,” Circulation Research, vol. 93, no. 3, pp. 221–229, 2003.
[44]
J. L. Brockdorff, H. Gu, T. Mustelin et al., “Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and stat5a,” Experimental and Clinical Immunogenetics, vol. 18, no. 2, pp. 86–95, 2001.
[45]
M. Gadina, C. Sudarshan, R. Visconti et al., “The docking molecule Gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common γ chain-using cytokines,” The Journal of Biological Chemistry, vol. 275, no. 35, pp. 26959–26966, 2000.
[46]
M. Gadina, C. Sudarshan, and J. J. O'Shea, “IL-2, but not IL-4 and other cytokines, induces phosphorylation of a 98- kDa protein associated with SHP-2, phosphatidylinositol 3'-kinase, and Grb2,” Journal of Immunology, vol. 162, no. 4, pp. 2081–2086, 1999.
[47]
F. Gesbert, C. Guenzi, and J. Bertoglio, “A new tyrosine-phosphorylated 97-kDa adaptor protein mediates interleukin-2-induced association of SHP-2 with p85-phosphatidylinositol 3- kinase in human T lymphocytes,” The Journal of Biological Chemistry, vol. 273, no. 29, pp. 18273–18281, 1998.
[48]
W. M. Yu, T. S. Hawley, R. G. Hawley, and C. K. Qu, “Role of the docking protein Gab2 in β1-integrin signaling pathway-mediated hematopoietic cell adhesion and migration,” Blood, vol. 99, no. 7, pp. 2351–2359, 2002.
[49]
B. L. Craddock, J. Hobbs, C. E. Edmead, and M. J. Welham, “Phosphoinositide 3-kinase-dependent regulation of interleukin-3-induced proliferation: involvement of mitogen-activated protein kinases, SHP2 and Gab2,” The Journal of Biological Chemistry, vol. 276, no. 26, pp. 24274–24283, 2001.
[50]
B. L. Craddock, E. A. Orchiston, H. J. Hinton, and M. J. Welham, “Dissociation of apoptosis from proliferation, protein kinase B activation, and BAD phosphorylation in interleukin-3-mediated phosphoinositide 3-kinase signaling,” Journal of Biological Chemistry, vol. 274, no. 15, pp. 10633–10640, 1999.
[51]
B. L. Craddock and M. J. Welham, “Interleukin-3 induces association of the protein-tyrosine phosphatase SHP2 and phosphatidylinositol 3-kinase with a 100-kDa tyrosine-phosphorylated protein in hemopoietic cells,” The Journal of Biological Chemistry, vol. 272, no. 46, pp. 29281–29289, 1997.
[52]
W. M. Yu, T. S. Hawley, R. G. Hawley, and C. K. Qu, “Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling,” Oncogene, vol. 22, no. 38, pp. 5995–6004, 2003.
[53]
W. J. Tao, H. Lin, T. Sun, A. K. Samanta, and R. Arlinghaus, “BCR-ABL oncogenic transformation of NIH 3T3 fibroblasts requires the IL-3 receptor,” Oncogene, vol. 27, no. 22, pp. 3194–3200, 2008.
[54]
Y. Miyakawa, P. Rojnuckarin, T. Habib, and K. Kaushansky, “Thrombopoietin induces phosphoinositol 3-kinase activation through SHP2, Gab, and insulin receptor substrate proteins in BAF3 cells and primary murine megakaryocytes,” The Journal of Biological Chemistry, vol. 276, no. 4, pp. 2494–2502, 2001.
[55]
D. Bouscary, C. Lecoq-Lafon, S. Chretien et al., “Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo),” Oncogene, vol. 20, no. 18, pp. 2197–2204, 2001.
[56]
H. Kojima, A. Shinagawa, S. Shimizu et al., “Role of phosphatidylinositol-3 kinase and its association with Gab1 in thrombopoietin-mediated up-regulation of platelet function,” Experimental Hematology, vol. 29, no. 5, pp. 616–622, 2001.
[57]
P. Rojnuckarin, Y. Miyakawa, N. E. Fox, J. Deou, G. Daum, and K. Kaushansky, “The roles of phosphatidylinositol 3-kinase and protein kinase Cζ for thrombopoietin-induced mitogen-activated protein kinase activation in primary murine megakaryocytes,” Journal of Biological Chemistry, vol. 276, no. 44, pp. 41014–41022, 2001.
[58]
M. Kong, C. Mounier, J. Wu, and B. I. Posner, “Epidermal growth factor-induced phosphatidylinositol 3-kinase activation and DNA synthesis: identification of Grb2-associated binder 2 as the major mediator in rat hepatocytes,” Journal of Biological Chemistry, vol. 275, no. 46, pp. 36035–36042, 2000.
[59]
M. Kong, C. Mounier, A. Balbis, G. Baquiran, and B. I. Posner, “Gab2 tyrosine phosphorylation by a pleckstrin homology domain-independent mechanism: role in epidermal growth factor-induced mitogenesis,” Molecular Endocrinology, vol. 17, no. 5, pp. 935–944, 2003.
[60]
J. Sun, M. Pedersen, and L. Ronnstrand, “Gab2 is involved in differential phosphoinositide 3-kinase signaling by two splice forms of c-Kit,” Journal of Biological Chemistry, vol. 283, no. 41, pp. 27444–27451, 2008.
[61]
H. Yoshihara, F. Arai, K. Hosokawa et al., “Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche,” Cell Stem Cell, vol. 1, no. 6, pp. 685–697, 2007.
[62]
M. Itoh, Y. Yoshida, K. Nishida, M. Narimatsu, M. Hibi, and T. Hirano, “Role of Gab l in heart, placenta, and skin development and growth factor—and cytokine-induced extracellular signal-regulated kinase mitogen—activated protein kinase activation,” Molecular and Cellular Biology, vol. 20, no. 10, pp. 3695–3704, 2000.
[63]
M. Sachs, H. Brohmann, D. Zechner et al., “Essential role of Gab1 for signaling by the c-Met receptor in vivo,” The Journal of Cell Biology, vol. 150, no. 6, pp. 1375–1384, 2000.
[64]
D. W. Threadgill, A. A. Dlugosz, L. A. Hansen et al., “Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype,” Science, vol. 269, no. 5221, pp. 230–234, 1995.
[65]
L. Karlsson, C. Bondjers, and C. Betsholtz, “Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle,” Development, vol. 126, no. 12, pp. 2611–2621, 1999.
[66]
P. Leveen, M. Pekny, S. Gebre-Medhin, B. Swolin, E. Larsson, and C. Betsholtz, “Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities,” Genes & Development, vol. 8, no. 16, pp. 1875–1887, 1994.
[67]
F. Bladt, D. Riethmacher, S. Isenmann, A. Aguzzi, and C. Birchmeier, “Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud,” Nature, vol. 376, no. 6543, pp. 768–771, 1995.
[68]
C. Schmidt, F. Bladt, S. Goedecke et al., “Scatter factor/hepatocyte growth factor is essential for liver development,” Nature, vol. 373, no. 6516, pp. 699–702, 1995.
[69]
R. Ohlsson, P. Falck, M. Hellstrom et al., “PDGFB regulates the development of the labyrinthine layer of the mouse fetal placenta,” Developmental Biology, vol. 212, no. 1, pp. 124–136, 1999.
[70]
C. K. Qu, W. M. Yu, B. Azzarelli, S. Cooper, H. E. Broxmeyer, and G. S. Feng, “Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells,” Molecular and Cellular Biology, vol. 18, no. 10, pp. 6075–6082, 1998.
[71]
E. A. Bard-Chapeau, A. L. Hevener, S. Long, E. E. Zhang, J. M. Olefsky, and G. S. Feng, “Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action,” Nature Medicine, vol. 11, no. 5, pp. 567–571, 2005.
[72]
H. Gu, K. Saito, L. D. Klaman et al., “Essential role for Gab2 in the allergic response,” Nature, vol. 412, no. 6843, pp. 186–190, 2001.
[73]
C. P. Shelburne, M. E. McCoy, R. Piekorz et al., “Stat5 expression is critical for mast cell development and survival,” Blood, vol. 102, no. 4, pp. 1290–1297, 2003.
[74]
C. E. Edmead, B. C. Fox, C. Stace, N. Ktistakis, and M. J. Welham, “The pleckstrin homology domain of Gab-2 is required for optimal interleukin-3 signalsome-mediated responses,” Cellular Signalling, vol. 18, no. 8, pp. 1147–1155, 2006.
[75]
K. Nishida, S. Yamasaki, A. Hasegawa, et al., “Gab2, via PI-3K, regulates ARF1 in fcepsilonRI-mediated granule translocation and mast cell degranulation,” Journal of Immunology, vol. 187, no. 2, pp. 932–941, 2011.
[76]
Y. Zhang, E. Diaz-Flores, G. Li et al., “Abnormal hematopoiesis in Gab2 mutant mice,” Blood, vol. 110, no. 1, pp. 116–124, 2007.
[77]
R. P. Bourette, S. Arnaud, G. M. Myles, J. P. Blanchet, L. R. Rohrschneider, and G. Mouchiroud, “Mona, a novel hematopoietic-specific adaptor interacting with the macrophage colony-stimulating factor receptor, is implicated in monocyte/macrophage development,” The Embo Journal, vol. 17, no. 24, pp. 7273–7281, 1998.
[78]
M. Seiffert, J. M. Custodio, I. Wolf et al., “Gab3-deficient mice exhibit normal development and hematopoiesis and are immunocompetent,” Molecular and Cellular Biology, vol. 23, no. 7, pp. 2415–2424, 2003.
[79]
R. J. Daly, H. Gu, J. Parmar et al., “The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer,” Oncogene, vol. 21, no. 33, pp. 5175–5181, 2002.
[80]
M. Bentires-Alj, S. G. Gil, R. Chan et al., “A role for the scaffolding adapter GAB2 in breast cancer,” Nature Medicine, vol. 12, no. 1, pp. 114–121, 2006.
[81]
T. Brummer, D. Schramek, V. M. Hayes et al., “Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein,” The Journal of Biological Chemistry, vol. 281, no. 1, pp. 626–637, 2006.
[82]
Y. Ke, D. Wu, F. Princen et al., “Role of Gab2 in mammary tumorigenesis and metastasis,” Oncogene, vol. 26, no. 34, pp. 4951–4960, 2007.
[83]
H. L. Bennett, T. Brummer, A. Jeanes, A. S. Yap, and R. J. Daly, “Gab2 and src co-operate in human mammary epithelial cells to promote growth factor independence and disruption of acinar morphogenesis,” Oncogene, vol. 27, no. 19, pp. 2693–2704, 2008.
[84]
J. M. Stommel, A. C. Kimmelman, H. Ying et al., “Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies,” Science, vol. 318, no. 5848, pp. 287–290, 2007.
[85]
V. de Falco, V. Guarino, L. Malorni et al., “RAI(ShcC/N-Shc)-dependent recruitment of GAB1 to RET oncoproteins potentiates PI3-K signalling in thyroid tumors,” Oncogene, vol. 24, no. 41, pp. 6303–6313, 2005.
[86]
S. H. Lee, E. G. Jeong, S. W. Nam, J. Y. Lee, N. J. Yoo, and S. H. Lee, “Increased expression of Gab2, a scaffolding adaptor of the tyrosine kinase signalling, in gastric carcinomas,” Pathology, vol. 39, no. 3, pp. 326–329, 2007.
[87]
M. Sattler, M. G. Mohi, Y. B. Pride et al., “Critical role for Gab2 in transformation by BCR/ABL,” Cancer Cell, vol. 1, no. 5, pp. 479–492, 2002.
[88]
H. E. Teal, S. Ni, J. Xu et al., “GRB2-mediated recruitment of GAB2, but not GAB1, to SF-STK supports the expansion of friend virus-infected erythroid progenitor cells,” Oncogene, vol. 25, no. 17, pp. 2433–2443, 2006.
[89]
C. Voena, C. Conte, C. Ambrogio et al., “The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration,” Cancer Research, vol. 67, no. 9, pp. 4278–4286, 2007.
[90]
K. Masson, T. Liu, R. Khan, J. Sun, and L. Ronnstrand, “A role of Gab2 association in Flt3 ITD mediated stat5 phosphorylation and cell survival,” British Journal of Haematology, vol. 146, no. 2, pp. 193–202, 2009.
[91]
A. Zatkova, C. Schoch, F. Speleman et al., “GAB2 is a novel target of 11q amplification in AML/MDS,” Genes Chromosomes & Cancer, vol. 45, no. 9, pp. 798–807, 2006.
[92]
V. M. Zaleskas, D. S. Krause, K. Lazarides et al., “Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F,” Plos One, vol. 1, no. 1, article e18, 2006.
[93]
K. Mood, C. Saucier, Y. S. Bong, H. S. Lee, M. Park, and I. O. Daar, “Gab1 is required for cell cycle transition, cell proliferation, and transformation induced by an oncogenic met receptor,” Molecular Biology of the Cell, vol. 17, no. 9, pp. 3717–3728, 2006.
[94]
M. Holgado-Madruga and A. J. Wong, “Role of the Grb2-associated binder 1/SHP-2 interaction in cell growth and transformation,” Cancer Research, vol. 64, no. 6, pp. 2007–2015, 2004.
[95]
A. Felici, A. Giubellino, and D. P. Bottaro, “Gab1 mediates hepatocyte growth factor-stimulated mitogenicity and morphogenesis in multipotent myeloid cells,” Journal of Cellular Biochemistry, vol. 111, no. 2, pp. 310–321, 2010.
[96]
S. Roumiantsev, D. S. Krause, C. A. Neumann et al., “Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations,” Cancer Cell, vol. 5, no. 3, pp. 287–298, 2004.
[97]
M. Scherr, A. Chaturvedi, K. Battmer et al., “Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML),” Blood, vol. 107, no. 8, pp. 3279–3287, 2006.
[98]
M. H. Nguyen, J. M. Ho, B. K. Beattie, and D. L. Barber, “TEL-JAK2 mediates constitutive activation of the phosphatidylinositol 3'-kinase/protein kinase B signaling pathway,” The Journal of Biological Chemistry, vol. 276, no. 35, pp. 32704–32713, 2001.
[99]
R. P. Million, N. Harakawa, S. Roumiantsev, L. Varticovski, and R. A. Van Etten, “A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase,” Molecular and Cellular Biology, vol. 24, no. 11, pp. 4685–4695, 2004.
[100]
D. Xu, S. Wang, W. M. Yu et al., “A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells,” Blood, vol. 116, no. 18, pp. 3611–3621, 2010.
[101]
Y. Yuan, L. Qin, D. Liu et al., “Genetic screening reveals an essential role of p27kip1 in restriction of breast cancer progression,” Cancer Research, vol. 67, no. 17, pp. 8032–8042, 2007.
[102]
M. T. Abreu, W. E. Hughes, K. Mele, et al., “Gab2 regulates cytoskeletal organization and migration of mammary epithelial cells by modulating RhoA activation,” Molecular Biology of the Cell, vol. 22, no. 1, pp. 105–116, 2011.
[103]
K. Abe, K. L. Rossman, B. Liu et al., “Vav2 is an activator of Cdc42, Rac1, and RhoA,” The Journal of Biological Chemistry, vol. 275, no. 14, pp. 10141–10149, 2000.
[104]
F. Bernal, M. Wade, M. Godes et al., “A stapled p53 helix overcomes HDMX-mediated suppression of p53,” Cancer Cell, vol. 18, no. 5, pp. 411–422, 2010.
[105]
C. R. Braun, J. Mintseris, E. Gavathiotis, G. H. Bird, S. P. Gygi, and L. D. Walensky, “Photoreactive stapled BH3 peptides to dissect the BCL-2 family interactome,” Chemistry & Biology, vol. 17, no. 12, pp. 1325–1333, 2010.
