receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) control a wide variety of processes in multicellular organisms, including proliferation, differentiation, migration and survival.

Their activity is tightly controlled through the coordinated action of both positive and negative regulators that function at multiple levels of the signal transduction cascade, and at different time points within the growth-factor-induced response. When this process goes awry, the outcome can be developmental defects and malignancy.

It is known that the bigger expression of the tyrosin kinase receptors in tumors is associated with an aggressive phenotype. For example overexpression of ephA2 or EGFR.

Activation of RTKs

The activation of Tyrosin Kinase Receptors (RTKs) produces several effects about cellular response. These are membrane receptors that bind differentiation signals, grow factors and cellular mediators. The interaction with their ligand causes the phosphorilation and internalization in the endosome.

By a metabolic way, these receptors are degradated into the proteasome to small peptides that are expressed over the cellular surface joined to MHC class I mollecules, getting a better immunogenic recognition of the tumor cells.

Types

 Src kinases family
 ephrins (EPHs) and ephrin receptors (EPHRs)
 sprouty proteins
 type 3 receptor tyrosine kinases (type 3 RTKs)

Mutations

 loss-of-function mutations
 gain-of-function mutations

Pathology

 dwarfism
 craniosynostosis
 heritable cancer susceptibility syndromes
 venous malformation
 piebaldism
 cancer

• The deregulation of tyrosine kinase receptors (RTKs) is frequent in human tumors and is often associated with the acquisition of an aggressive phenotype.

References

 Lengyel E, Sawada K, Salgia R. Tyrosine kinase mutations in human cancer. Curr Mol Med. 2007 Feb;7(1):77-84. PMID: 17311534

 Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005 Jul 14;353(2):172-87. PMID: 16014887

 Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer. 2004 May;4(5):361-70. PMID: 15122207

 Gu H, Neel BG. The ’Gab’ in signal transduction. Trends Cell Biol. 2003 Mar;13(3):122-30. PMID: 12628344

 Zwick E, Bange J, Ullrich A. Receptor tyrosine kinases as targets for anticancer drugs. Trends Mol Med. 2002 Jan;8(1):17-23. PMID: 11796262

 Ostman A, Bohmer FD. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol. 2001 Jun;11(6):258-66. PMID: 11356362

 Robertson SC, Tynan JA, Donoghue DJ. RTK mutations and human syndromes when good receptors turn bad. Trends Genet. 2000 Jun;16(6):265-71. PMID: 10827454

 Tan PB, Kim SK. Signaling specificity: the RTK/RAS/MAP kinase pathway in metazoans. Trends Genet. 1999 Apr;15(4):145-9. PMID: 10203824