Abnormalities in cell signaling pathways in sPNETs14:
1. Ras ‘superfamily’
The Ras superfamily of proteins are small GTPases involved in cell proliferation, differentiation and survival.
A GTPase protein is able to switch a signal transduction chain on or off depending if it is in the active (GTP bound) state or the inactive (GDP bound) state.
In cases where these proteins are constitutively activated, it can result in uncontrolled cell proliferation or failure of apoptosis, thus causing formation of a tumor.
The Rho protein family is a subset of the Ras family of GTPases that are also responsible for many cellular processes including cell proliferation.
Rho proteins are controlled by 3 types of regulatory proteins:
- Guanine nucleotide exchange factors (GEFs)
- GTPase activating proteins (GAPs)
- Guanine nucleotide dissociation inhibitors (GDIs)
Dysregulation of any of the regulatory proteins or of the Rho protein itself can result in a constitutively active state that may contribute to the formation of tumors
Example: The gene, DLC-1, can be hypermethylated, resulting in downregulation of the protein RhoGAP, which is responsible for decreasing the activity of Rho GTPase. Therefore, Rho GTPase is constitutively activated, thus causing an increase in cell proliferation.
Link: The Ras superfamily at a glance Krister Wennerberg, Kent L. Rossman and Channing J. Der (Journal of cell science).
2. Sonic hedgehog-Gli (Shh-Gli)
Shh protein stimulates an intracellular signal transduction pathway that contributes to the differentiation of many organs in the developing embryo, including, the notochord, floor plate and limbs3
Gli protein is the primary mediator of transcriptional activation by Shh
Dysregulation leads to downstream decreased tumor suppression
Link: Hedgehog signaling pathway: an overview by Dr Claudie Hooper
3. Wingless (Wnt)
The wnt signaling pathway is also implicated in the development of the neural tube
4. Notch-Hes
