2. Activation of receptor tyrosine kinases in diseases
Activation of receptor tyrosine kinases, including FGF and PDGF receptors, is often associated with cancer development. Genetic alterations in FGF and PDGF receptors have been found in several types of tumors (see Figure below). Activation of PDGF receptors was also found in metastatic medulloblastoma and breast cancer.
Alteration in PDGF receptors in cancer
|
Alteration |
Cancer type |
1 |
Autocrine |
Dermatofibrosarcoma |
2 |
PDGFRA mutations |
Gastrointestinal stromal tumors |
3 |
Hybrid receptors created by chromosomal translocations |
Myeloid neoplasms associated with eosinophilia |
4 |
Hybrid receptors created by chromosomal deletion |
Chronic eosinophilic leukemia |
5 |
Gene amplification |
Glioma |
We have characterized a new translocation product between the PDGF receptor beta and KANK1, a potential tumor suppressor gene, in a patient with severe thrombocythemia (Medves et al, 2010).
In order to transform cells, PDGF receptors must be constitutively activated and escape degradation. We have studied the degradation of several PDGF receptor hybrids, which are found in leukemia. We observed that these hybrids are very stable compared to activated wild type receptors, which are quickly degraded by lysosomes (Toffalini et al, 2009). We are now analyzing the mechanism of ubiquitination and degradation of oncogenic tyrosine kinases.
We are also interested in the role of PDGF receptors in other diseases such as systemic sclerosis (Classen et al, 2009).
Publications and supplementary material:
Medves S, Duhoux FP, Ferrant A, Toffalini F, Ameye G, Libouton JM, Poirel HA, Demoulin JB. KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia. Leukemia 2010, 24:1052-55.
Toffalini F, Hellberg C, Demoulin JB.
Critical role of the platelet-derived growth factor receptor (PDGFR) beta transmembrane domain in the TEL-PDGFRbeta cytosolic oncoprotein.
J Biol Chem. 2010, 285:12268-78.
Toffalini F, Kallin A, Michaux L, Vandenberghe P, Pierre P, Cools J and Demoulin JB.
The fusion proteins TEL-PDGFRβ and FIP1L1-PDGFRα escape ubiquitination and degradation.
Haematologica 2009, 94:1085.
Classen JF, Henrohn D, Rorsman F, Lennartsson J, Lauwerys BR, Wikström G, Rorsman C, Lenglez S, Franck-Larsson K, Tomasi JP, Kämpe O, Vanthuyne M, Houssiau FA, Demoulin JB.
Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis.
Arthritis Rheum. 2009, 60:1137-44.
Supplementary material
Demoulin JB, Kämpe O, Rorsman F.
Scleroderma.
N Engl J Med. 2009, 361:826
To know more... (pdf chapter of the last de Duve Institute report)
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