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Item EGFL6 regulates the asymmetric division, maintenance and metastasis of ALDH+ ovarian cancer cells(American Association for Cancer Research, 2016-11-01) Bai, Shoumei; Ingram, Patrick; Chen, Yu-Chih; Deng, Ning; Pearson, Alex; Niknafs, Yashar; O'Hayer, Patrick; Wang, Yun; Zhang, Zhong-Yin; Boscolo, Elisa; Bischoff, Joyce; Yoon, Euisik; Buckanovich, Ronald J; Biochemistry and Molecular Biology, School of MedicineLittle is known about the factors that regulate the asymmetric division of cancer stem-like cells. Here we demonstrate that EGFL6, a stem cell regulatory factor expressed in ovarian tumor cells and vasculature, regulates ALDH+ ovarian cancer stem-like cells (CSC). EGFL6 signaled at least in part via the oncoprotein SHP2 with concomitant activation of ERK. EGFL6 signaling promoted the migration and asymmetric division of ALDH+ ovarian CSC. As such, EGFL6 increased not only tumor growth but also metastasis. Silencing of EGFL6 or SHP2 limited numbers of ALDH+ cells and reduced tumor growth, supporting a critical role for EGFL6/SHP2 in ALDH+ cell maintenance. Notably, systemic administration of an EGFL6-neutralizing antibody we generated restricted tumor growth and metastasis, specifically blocking ovarian cancer cell recruitment to the ovary. Together, our results offer a preclinical proof of concept for EGFL6 as a novel therapeutic target for the treatment of ovarian cancer.Item Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus(American Society for Clinical Investigation, 2016-06-01) Wang, Jianxun; Mizui, Masayuki; Zeng, Li-Fan; Bronson, Roderick; Finnell, Michele; Terhorst, Cox; Kyttaris, Vasileios C.; Tsokos, George C.; Zhang, Zhong-Yin; Kontaridis, Maria I.; Department of Biochemistry & Molecular Biology, IU School of MedicineSystemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain–containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-γ and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-γ and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients.Item Rapid development of myeloproliferative neoplasm in mice with Ptpn11D61Y mutation and haploinsufficient for Dnmt3a(Impact Journals, 2017-12-26) Deng, Lisa; Richine, Briana M.; Virts, Elizabeth L.; Jideonwo-Auman, Victoria N.; Chan, Rebecca J.; Kapur, Reuben; Pediatrics, School of MedicinePTPN11 gain-of-function mutation is the most common mutation found in patients with juvenile myelomonocytic leukemia and DNMT3A loss occurs in over 20% of acute myeloid leukemia patients. We studied the combined effect of both Ptpn11 gain-of-function mutation (D61Y) and Dnmt3a haploinsufficiency on mouse hematopoiesis, the presence of which has been described in both juvenile myelomonocytic leukemia and acute myeloid leukemia patients. Double mutant mice rapidly become moribund relative to any of the other genotypes, which is associated with enlargement of the spleen and an increase in white blood cell counts. An increase in the mature myeloid cell compartment as reflected by the presence of Gr1+Mac1+ cells was also observed in double mutant mice relative to any other group. Consistent with these observations, a significant increase in the absolute number of granulocyte macrophage progenitors (GMPs) was seen in double mutant mice. A decrease in the lymphoid compartment including both T and B cells was noted in the double mutant mice. Another significant difference was the presence of extramedullary erythropoiesis with increased erythroid progenitors in the spleens of Dnmt3a+/-;D61Y mice relative to other groups. Taken together, our results suggest that the combined haploinsufficiency of Dnmt3a and presence of an activated Shp2 changes the composition of multiple hematopoietic lineages in mice relative to the individual heterozygosity of these genes.Item Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2(Society for Neuroscience, 1999-11-01) Tanowitz, Michael; Si, Jutong; Yu, De-Hua; Feng, Gen-Sheng; Mei, Lin; Biochemistry and Molecular Biology, School of MedicineSynapse-specific expression of the nicotinic acetylcholine receptor (AChR) is believed to be mediated by neuregulin, an epidermal growth factor-like trophic factor released by somatic motoneurons at the neuromuscular junction (NMJ). Neuregulin stimulates ErbB2, ErbB3, and ErbB4, members of the ErbB family of receptor tyrosine kinases. SHP2 is a cytoplasmic protein tyrosine phosphatase containing two Src homology 2 domains near its N terminus, and has been shown to be a positive mediator of mitogenic responses to various growth factors. We found that SHP2 interacted with ErbB2 and ErbB3 after neuregulin stimulation of muscle cells. Expression of SHP2 in C2C12 mouse muscle cells attenuated the neuregulin-induced expression of an AChR epsilon-promoter reporter gene, whereas a catalytically inactive SHP2 mutant or a mutant lacking the N-terminal Src homology 2 (SH2) domain enhanced reporter expression, suggesting that SHP2 negatively regulates the neuregulin signaling pathway. In fibroblast cells that express a mutant SHP2 with a targeted deletion of the N-terminal SH2 domain, neuregulin-mediated activation of the Ras/Raf/extracellular signal-regulated kinase cascade was enhanced. Furthermore, we found that SHP2 immunoreactivity colocalized with the staining of alpha-bungarotoxin, a marker of the NMJ. These results demonstrate a negative role of SHP2 in the neuregulin signal that leads to AChR gene expression at the NMJ.Item Role of SHP2 in hematopoiesis and leukemogenesis(Wolters Kluwer, 2017-07) Pandey, Ruchi; Saxena, Mallika; Kapur, Reuben; Pediatrics, School of MedicinePurpose of review SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrant hematopoiesis along with novel strategies to target it. Recent findings Cell autonomous role of SHP2 in normal hematopoiesis and leukemogenesis has long been recognized. The review will discuss the newly discovered role of SHP2 in lineage specific differentiation. Recently, a noncell autonomous role of oncogenic SHP2 has been reported in which activated SHP2 was shown to alter the bone marrow microenvironment resulting in transformation of donor derived normal hematopoietic cells and development of myeloid malignancy. From being considered as an ‘undruggable’ target, recent development of allosteric inhibitor has made it possible to specifically target SHP2 in receptor tyrosine kinase driven malignancies. Summary SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and microenvironmental effects. However a better understanding of the role of SHP2 in different hematopoietic lineages and its crosstalk with signaling pathways activated by other genetic lesions is required before the promise is realized in the clinic.Item SHP2 phosphatase as a novel therapeutic target for melanoma treatment(Impact Journals, 2016-11-08) Zhang, Ruo-Yu; Yu, Zhi-Hong; Zeng, Lifan; Zhang, Sheng; Bai, Yunpeng; Miao, Jinmin; Chen, Lan; Xie, Jingwu; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of MedicineMelanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.Item Targeting SHP2 phosphatase in hematological malignancies(Taylor & Francis, 2022) Kanumuri, Rahul; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Ramdas, Baskar; Kapur, Reuben; Pediatrics, School of MedicineIntroduction: Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed, non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. Gain-of-function (GOF) mutations in PTPN11 are associated with the development of various hematological malignancies and Noonan syndrome with multiple lentigines (NS-ML). Preclinical studies performed with allosteric SHP2 inhibitors and combination treatments of SHP2 inhibitors with inhibitors of downstream regulators (such as MEK, ERK, and PD-1/PD-L1) demonstrate improved antitumor benefits. However, the development of novel SHP2 inhibitors is necessary to improve the therapeutic strategies for hematological malignancies and tackle drug resistance and disease relapse. Areas covered: This review examines the structure of SHP2, its function in various signaling cascades, the consequences of constitutive activation of SHP2 and potential therapeutic strategies to treat SHP2-driven hematological malignancies. Expert opinion: While SHP2 inhibitors have exhibited promise in preclinical trials, numerous challenges remain in translation to the clinic, including drug resistance. Although PROTAC-based SHP2 degraders show better efficacy than SHP2 inhibitors, novel strategies need to be designed to improve SHP2-specific therapies in hematologic malignancies. Genome-wide CRISPR screening should also be used to identify molecules that confer resistance to SHP2 inhibitors. Targeting these molecules together with SHP2 can increase the target specificity and reduce drug resistance.