Abstract
Rab11-FIP1 is a Rab effector protein that is involved in endosomal recycling and trafficking of various molecules throughout the endocytic compartments of the cell. The consequence of this can be increased secretion or increased membrane expression of those molecules. In general, expression of Rab11-FIP1 coincides with more tumourigenic and metastatic cell behaviour. Rab11-FIP1 can work in concert with oncogenes such as mutant p53, but has also been speculated to be an oncogene in its own right. In this perspective, we will discuss and speculate upon our observations that mutant p53 promotes Rab11-FIP1 function to not only promote invasive behaviour, but also chemoresistance by regulating a multitude of different proteins.
Highlights
Rab11-FIP1 was identified as a downstream effector and interactor of the Rab-GTPase Rab11a, important in membrane recycling systems [1]
We have shown previously that mutant p53 inhibits TAp63a function, and in those same conditions, mutant p53 promotes the interaction between integrins, Receptor Tyrosine Kinase (RTK) and the Rab-coupling protein/Rab11-Family Interacting Protein 1 (RCP/Rab11-FIP1), leading to increased invasion, cell scattering, metastasis and chemoresistance [16,17,18]
As we demonstrated that mutant p53 through Rab11-FIP1 could promote recycling of both Epidermal Growth Factor (EGFR) and c-Met, it is tempting to consider that other RTKs are regulated in this manner
Summary
Rab11-FIP1 was identified as a downstream effector and interactor of the Rab-GTPase Rab11a, important in membrane recycling systems [1]. Perhaps by both regulating expression as well as actual plasma membrane expression, something that is likely occurring for b1 integrin [32], mutant p53 could facilitate an amplified cell signalling response that promotes metastastic behaviour and causes the multidrug chemoresistance that is often seen in mutant p53 tumours Taken together, these data demonstrate that mutant p53 can regulate integrin/RTK signalling in a Rab11-FIP1-dependent manner to promote invasion and metastasis. Loss of Rab11-FIP1 appeared not to limit the amount of ATP7B expressed on the plasma membrane in response to copper (Figure 2D) and Rab11-FIP1 KO cells were not more sensitive to copper exposure (Figure 2E) These data could indicate that the type of external stimulus (in this case chemotherapeutics, but not copper) dictates Rab11FIP1 activity. Those work best in a setting of mutant p53 and Rab11FIP1 in which cancer cells are dependent or even addicted to the amplified signalling
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