RTKs - Receptor Tyrosine Kinases
Protein Phosphorylation

Author: Gianpiero Pescarmona
Date: 30/04/2009

Description

Receptor tyrosine kinases are a large family of transmembrane proteins with diverse extracellular ligand-binding structures, but which all possess a highly conserved domain with intrinsic tyrosine kinase activity.

Intracellular signalling is triggered through activation of the tyrosine kinase domain and its subsequent phosphorylation of multiple substrates. Subfamilies of RTKs are categorised according to their amino acid sequence identities and extracellular structural similarities; thus members of a subfamily often bind common or similar ligands. In humans, 20 distinct subfamilies of RTKs exist that are categorized according to their amino-acid sequence identities and structural similarities in their extracellular regions

Approximately 20 different RTK classes have been identified

  1. RTK class I (EGF receptor family)(ErbB family)
  2. RTK class II (Insulin receptor family)
  3. RTK class III (PDGF receptor family)
  4. RTK class IV (FGF receptor family)
  5. RTK class V (VEGF receptors family)
  6. RTK class VI (HGF receptor family)
  7. RTK class VII (Trk receptor family)
  8. RTK class VIII (Eph receptor family)
  9. RTK class IX (AXL receptor family)
  10. RTK class X (LTK receptor family)
  11. RTK class XI (TIE receptor family)
  12. RTK class XII (ROR receptor family)
  13. RTK class XIII (DDR receptor family)
  14. RTK class XIV (RET receptor family)
  15. RTK class XV (KLG receptor family)
  16. RTK class XVI (RYK receptor family)
  17. RTK class XVII (MuSK receptor family)

Ligand Proteins Information Content

Analysis of AA content of RTKs ligands can give useful information about their information content.

Additional factors are :

  • ligands release modulation
  • ligands half life

Comments
2010-09-13T19:05:20 - Gianpiero Pescarmona

ALK Shc

  • SRC, JAK, STAT3
  • Sos, Ras, Erk-Jnk
2010-09-13T18:50:55 - Gianpiero Pescarmona

ALK

The anaplastic lymphoma kinase in the pathogenesis of cancer 2008

more links

Pathobiology of ALK+ anaplastic large-cell lymphoma 2007

Signalling via dALK occurs via binding of the ligand Jeb, downstream activation of ERK and transcription of downstream target genes. Signalling via mammalian ALK is thought to occur via ligand-mediated dimerization in response to the MK and PTN ligands. ALK mediates signalling via the JAK/STAT, RAS/MAPK, PI3K and PLCγ pathways. Activation of ALK via RPTPβ/ζ, independently of direct ALK–ligand interactions has also been proposed. Lastly, ALK is proposed to function as a dependency receptor which is cleaved by caspase 3 (Casp. 3) in the absence of ligand, thereby promoting apoptosis.

Ligands

In mammals PTN (pleiotrophin) also known as HB-GAM (heparin-binding growth-associated molecule) [39], OSF-1 (osteoblast-specific factor-1) [40], HARP (heparin affinity regulatory peptide) [41] and HBNF (heparin-binding neurotrophic factor) [42]; and MK (midkine) [43], also known as RIHB (retinoic acid-inducible heparin-binding protein) [44], have been postulated to be the activating ligands for ALK [6,45]. MK and PTN are small, heparin-binding growth factors implicated in diverse processes such as neural development, cell migration and angiogenesis [46,47]. The observation that PTN could function as a ligand for ALK arises from the isolation of a small portion of the extracellular region of ALK which was identified upon screening a human foetal brain phage display cDNA library for PTN-binding partners [6]. Subsequently, the PTN-related protein MK was identified as an ALK ligand. Furthermore, antibodies directed toward the ALK extracellular domain could inhibit the in vitro ligand–receptor interaction, suggesting that MK and PTN bind ALK

Anaplastic lymphoma kinase: signalling in development and disease 2009

PTN and MK have high lysine; that could correspond to low histones

Coupling histone homeostasis to centromere integrity via the ubiquitin-proteasome system 2010

Suppression of lung adenocarcinoma through menin and polycomb gene-mediated repression of growth factor pleiotrophinMenin suppresses lung cancer through PTN 2009

ALK and its ligands bear different info about AA

while ALK and MEN1 (menin) are very similar.

and lack some AA necessary for cell cycle. For that reason MEN1 is an oncosuppressor.

Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. 2008

Menin, the product of the Men1 gene mutated in familial multiple endocrine neoplasia type 1 (MEN1), regulates transcription in differentiated cells. Menin associates with and modulates the histone methyltransferase activity of a nuclear protein complex to activate gene expression. However, menin-dependent histone methyltransferase activity in endocrine cells has not been demonstrated, and the mechanism of endocrine tumor suppression by menin remains unclear. Here, we show that menin-dependent histone methylation maintains the in vivo expression of cyclin-dependent kinase (CDK) inhibitors to prevent pancreatic islet tumors. In vivo expression of CDK inhibitors, including p27 and p18, and other cell cycle regulators is disrupted in mouse islet tumors lacking menin. Chromatin immunoprecipitation studies reveal that menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in histone H3 associated with these promoters. Moreover, H3 Lys-4 methylation associated with p27 and p18 is reduced in islet tumors from Men1 mutant mice. Thus, H3 Lys-4 methylation is a crucial function of menin in islet tumor suppression. These studies suggest an epigenetic mechanism of tumor suppression: by promoting histone modifications, menin maintains transcription at multiple loci encoding cell cycle regulators essential for endocrine growth control.

Genetic and Clinical Aspects of Primary Hyperparathyroidism: Inactivation of the MEN1 Gene - A Putative Tumour Suppressor Gene

Attachments
fileuserdate
ALK-Menin-700.gifgp13/09/2010
ALK-PTN-MK-CH2.gifgp13/09/2010
ALK-PTN-MK.gifgp13/09/2010
INS-PTN-700.gifgp19/09/2010
MEN1-PTN-MK-700.gifgp13/09/2010
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