Autocatalytic phosphorylation of overexpressed FGFR2 variants

Stable Identifier
R-HSA-2029989
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane, cytosol
ReviewStatus
5/5
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Autocatalytic phosphorylation of overexpressed FGFR2 variants
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Amplification of full length FGFR2 is only weakly transforming in NIH 3T3 cells, reflecting the presence of a putative transformation-inhibitory region in the c-terminus of the protein (Itoh, 1994, Cha, 2009). C-terminally truncated variants of FGFR2 that are preferrentially expressed in cancer show more potent transformation potential (Cha, 2008; Cha, 2009). These variants lack a number of carboxy-terminal tyrosine residues, including Y770 and Y773. Loss of Y770 contributes to transformation by enhancing FRS2 binding to the C-terminally truncated variant. This suggests that in the context of the full-length protein the presence of Y770 restricts access of FRS2 to the receptor. Loss or mutation of Y773 impairs internalization and degradation of the receptor and promotes sustained signaling (Cha, 2009). Gastric cancer cell lines with FGFR2 amplifications appear to undergo ligand-independent signaling and are sensitive to inhibition with ATP-competitive inhibitors (Takeda, 2007).


FGFR2 amplifications identified in 4% of triple negative breast cancers have also been shown to be constitutively active and to have elevated levels of phosphorylated FRS2 in the absence of ligand. Consistent with this, shRNA knockdown or chemical inhibition restricts proliferation and induces apoptosis in these cells (Kunii, 2008; Turner, 2010)

Literature References
PubMed ID Title Journal Year
18337450 Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis

Der, CJ, Cha, JY, Lambert, QT, Reuther, GW

Mol Cancer Res 2008
17505008 AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor

Fukuoka, K, Yamada, Y, Yanagihara, K, Nishio, K, Sasaki, H, Kimura, H, Takeda, M, Tamura, T, Komatsu, T, Yokote, H, Arao, T, Saijo, N

Clin Cancer Res 2007
20101236 Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets

Geyer, FC, van Kouwenhove, M, van de Vijver, MJ, Horlings, HM, Reis-Filho, JS, Ashworth, A, Lambros, MB, Natrajan, R, Sharpe, R, Turner, N, Kreike, B, Mackay, A, Pearson, A

Oncogene 2010
19103595 Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform

Der, CJ, Harden, TK, Mitin, N, Cha, JY, Maddileti, S

J Biol Chem 2009
8205545 Preferential alternative splicing in cancer generates a K-sam messenger RNA with higher transforming activity

Sakamoto, H, Kishi, T, Koono, M, Itoh, H, Ishii, H, Sasaki, H, Sugimura, T, Yoshida, T, Hattori, Y, Terada, M

Cancer Res 1994
18381441 FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival

Kunii, K, Gorenstein, J, Hatch, H, Lutterbach, B, Yashiro, M, Davis, L, Di Bacco, A, Elbi, C

Cancer Res 2008
Participants
Input
Output
Participates
as an event of
Catalyst Activity

protein tyrosine kinase activity of Overexpressed FGFR2 homodimers [plasma membrane]

Physical Entity
Overexpressed FGFR2 homodimers [plasma membrane] (Homo sapiens)
Activity
protein tyrosine kinase activity (GO:0004713)
Functional status

Gain of function of Overexpressed FGFR2 homodimers [plasma membrane]

Disease Entity
Status
Disease
Name Identifier Synonyms
stomach cancer DOID:10534 malignant neoplasm of greater curvature of stomach, unspecified, malignant neoplasm of lesser curvature of stomach, NOS, malignant tumor of body of stomach (disorder), neoplasm of stomach (disorder), Ca lesser curvature - stomach (disorder), malignant neoplasm of greater curve of stomach unspecified (disorder), Ca body - stomach, ca lesser curvature of stomach, ca greater curvature of stomach, malignant neoplasm of lesser curvature of stomach, unspecified, malignant tumor of lesser curve of stomach (disorder), malignant neoplasm of body of stomach, gastric neoplasm, malignant neoplasm of greater curvature of stomach, NOS, Ca body - stomach (disorder), stomach neoplasm, Ca greater curvature - stomach (disorder), malignant neoplasm of lesser curve of stomach unspecified (disorder), malignant tumor of greater curve of stomach (disorder)
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
breast cancer DOID:1612 malignant tumor of the breast, mammary cancer, malignant neoplasm of breast, mammary tumor, primary breast cancer, breast cancer, Ca breast - NOS, breast tumor
Authored
Rothfels, K  (2012-02-10)
Reviewed
Ezzat, S  (2012-05-15)
Created
Rothfels, K  (2012-01-05)
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