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The tyrosine phosphatase Shp2 (PTPN11) in cancer

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Abstract

Diverse cellular processes are regulated by tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). De-regulated tyrosyl phosphorylation, evoked by gain-of-function mutations and/or over-expression of PTKs, contributes to the pathogenesis of many cancers and other human diseases. PTPs, because they oppose the action of PTKs, had been considered to be prime suspects for potential tumor suppressor genes. Surprisingly, few, if any, tumor suppressor PTPs have been identified. However, the Src homology-2 domain-containing phosphatase Shp2 (encoded by PTPN11) is a bona fide proto-oncogene. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, whereas somatic PTPN11 mutations occur in several types of hematologic malignancies, most notably juvenile myelomonocytic leukemia and, more rarely, in solid tumors. Shp2 also is an essential component in several other oncogene signaling pathways. Elucidation of the events underlying Shp2-evoked transformation may provide new insights into oncogenic mechanisms and novel targets for anti-cancer therapy.

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Abbreviations

AGM:

aorta-gonad-mesonephros

ALCL:

anaplastic large cell lymphoma

AML:

acute myelogenous leukemia

B-ALL:

B-acute lymphoblastic leukemia

BM:

bone marrow

BMMs:

bone marrow macrophages

CagA:

cytoxin-associated antigen A

CFU:

colony forming unit

CML:

chronic myelogenous leukemia

CMML:

chronic myelomonocytic leukemia

FL:

fetal liver

FRS:

fibroblast growth factor receptor substrate

GAB:

GRB2-associated binders

ICSBP:

interferon consensus sequence binding protein

IRF8:

interferon response factor 8

IRS:

insulin receptor substrate

JMML:

juvenile myelomonocytic leukemia

LS:

LEOPARD syndrome

MDS:

myelodysplastic syndrome

MM:

multiple myeloma

MPD:

myeloproliferative disease

NS:

Noonan syndrome

NRPTPs:

non-receptor PTPs

PTKs:

protein-tyrosine kinases

PTPs:

protein-tyrosine phosphatases

pY:

Phosphotyrosyl

RTKs:

receptor tyrosine kinases

SFK:

Src family kinase

SH2:

Src homology-2

WT:

wild type

YS:

yolk sac

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  1. Ontario Cancer Institute, 101 College Street, TMDT Room 8-301, Toronto, Ontario, M5G 1L7, Canada

    Gordon Chan & Benjamin G. Neel

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 1030, Boston, MA, 02115, USA

    Demetrios Kalaitzidis

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Chan, G., Kalaitzidis, D. & Neel, B.G. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev 27, 179–192 (2008). https://doi.org/10.1007/s10555-008-9126-y

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