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The role of SRC-like adaptor protein 2 (SLAP2) in receptor tyrosine kinase KIT signaling

Rupar, Kaja (2016) MOBT01 20161
Degree Projects in Molecular Biology
Popular Abstract
SLAP2: A potential new strategy in fighting cancer

Among more than 20,000 genes in humans, about 2% of genes encode a class of proteins referred to as kinases. A kinase is a protein, which transfers phosphate groups to proteins called substrate proteins. This process is named phosphorylation and almost all cellular behaviors are controlled by protein phosphorylation. Kinases mainly phosphorylate their substrate proteins on three different amino acids such as serine, threonine and tyrosine. The human genome encodes around 90 protein kinases that phosphorylate tyrosine residues of their substrates and are therefore classified as protein tyrosine kinases (PTKs). Receptor tyrosine kinases (RTKs) are a subfamily of PTKs, involved in... (More)
SLAP2: A potential new strategy in fighting cancer

Among more than 20,000 genes in humans, about 2% of genes encode a class of proteins referred to as kinases. A kinase is a protein, which transfers phosphate groups to proteins called substrate proteins. This process is named phosphorylation and almost all cellular behaviors are controlled by protein phosphorylation. Kinases mainly phosphorylate their substrate proteins on three different amino acids such as serine, threonine and tyrosine. The human genome encodes around 90 protein kinases that phosphorylate tyrosine residues of their substrates and are therefore classified as protein tyrosine kinases (PTKs). Receptor tyrosine kinases (RTKs) are a subfamily of PTKs, involved in transducing extracellular signals into the cell.

The stem cell factor (SCF) receptor, KIT, is a receptor tyrosine kinase that regulates cell proliferation, survival and differentiation. Oncogenic mutations in KIT are found in many diseases including melanoma, breast cancer, acute myeloid leukemia (AML) and testicular carcinomas. There are several small molecule kinase inhibitors, which act against KIT and have shown promising results in clinical trials. Even though these inhibitors initially display promising results, some cancers develop resistance to treatment over time. Therefore, understanding how KIT mediates mitogenic signaling will facilitate identification of alternative drug targets in cancers.

Adaptor proteins are important regulators of RTK signaling. By binding to receptors, these proteins increase or inhibit signaling of the receptors through different mechanisms. Here we show a new adaptor protein, Src-like adaptor protein 2 (SLAP2), which binds to KIT and regulates its downstream signaling.

Normally, receptors need to bind their ligand in order to activate signaling cascades. However, oncogenic mutations that occur in receptors make the receptors ligand-independent. Therefore, the mutant receptors can constitutively activate signaling, which promotes cell survival. We observed that SLAP2 and KIT association occurs only when SCF, which is a KIT ligand, binds to the receptor. One of the oncogenic mutant of KIT, referred to as KIT-D816V, displayed a constitutive association with SLAP2, since KIT-D816V is constitutively activated. Expression of mutant KIT-D816V promotes activation of survival signaling. We could show that SLAP2 expression reduced the ability of KIT-D816V to promote cell proliferation and formation of colonies in semi-solid medium and also partially blocked KIT-mediated activation of downstream signaling pathways. This regulation is mediated by direct interaction between SLAP2 and KIT as this association enhanced degradation of the receptor. Altogether, we suggest that SLAP2 is important for maintaining basal KIT levels and normal KIT signaling, since loss of SLAP2 function leads to uncontrolled activation of KIT-mediated mitogenic signaling.

Supervisor: Julhash Uddin Kazi
Master Degree Project in Molecular Biology, 60 credits, 2016
Department of Biology, Lund University (Less)
Please use this url to cite or link to this publication:
author
Rupar, Kaja
supervisor
organization
course
MOBT01 20161
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8891890
date added to LUP
2016-09-16 08:48:18
date last changed
2016-09-16 08:48:18
@misc{8891890,
  author       = {Rupar, Kaja},
  language     = {eng},
  note         = {Student Paper},
  title        = {The role of SRC-like adaptor protein 2 (SLAP2) in receptor tyrosine kinase KIT signaling},
  year         = {2016},
}