scholarly journals Rab11-FIP1/RCP Functions as a Major Signalling Hub in the Oncogenic Roles of Mutant p53 in Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yannick von Grabowiecki ◽  
Vinaya Phatak ◽  
Lydia Aschauer ◽  
Patricia A. J. Muller
Keyword(s):  
General Expression ◽  
Effector Protein ◽  
Mutant P53 ◽  
Membrane Expression ◽  
Cell Behaviour ◽  
Metastatic Cell ◽  
Endosomal Recycling ◽  
Endocytic Compartments ◽  
Rab Effector

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.

scholarly journals Phagosomes Fuse with Late Endosomes and/or Lysosomes by Extension of Membrane Protrusions along Microtubules: Role of Rab7 and RILP

2003 ◽  
Vol 23 (18) ◽  
pp. 6494-6506 ◽  
Author(s):  
Rene E. Harrison ◽  
Cecilia Bucci ◽  
Otilia V. Vieira ◽  
Trina A. Schroer ◽  
Sergio Grinstein
Keyword(s):  
Innate Immune ◽  
Effector Protein ◽  
Motor Complex ◽  
Fluorescence And Electron Microscopy ◽  
Late Endosomes ◽  
Membrane Protrusions ◽  
Endocytic Compartments ◽  
Phagosomal Membrane ◽  
Lysosomal Protein

ABSTRACT Nascent phagosomes must undergo a series of fusion and fission reactions to acquire the microbicidal properties required for the innate immune response. Here we demonstrate that this maturation process involves the GTPase Rab7. Rab7 recruitment to phagosomes was found to precede and to be essential for their fusion with late endosomes and/or lysosomes. Active Rab7 on the phagosomal membrane associates with the effector protein RILP (Rab7-interacting lysosomal protein), which in turn bridges phagosomes with dynein-dynactin, a microtubule-associated motor complex. The motors not only displace phagosomes in the centripetal direction but, strikingly, promote the extension of phagosomal tubules toward late endocytic compartments. Fusion of tubules with these organelles was documented by fluorescence and electron microscopy. Tubule extension and fusion with late endosomes and/or lysosomes were prevented by expression of a truncated form of RILP lacking the dynein-dynactin-recruiting domain. We conclude that full maturation of phagosomes requires the retrograde emission of tubular extensions, which are generated by activation of Rab7, recruitment of RILP, and consequent association of phagosomes with microtubule-associated motors.

scholarly journals Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Vinaya Phatak ◽  
Yannick von Grabowiecki ◽  
Justyna Janus ◽  
Leah Officer ◽  
Caron Behan ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinases ◽  
Mutant P53 ◽  
Interacting Proteins ◽  
Wild Type ◽  
Glycoprotein P ◽  
P53 Expression ◽  
P Glycoprotein ◽  
Endosomal Recycling ◽  
Coupling Protein

AbstractTP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.

scholarly journals bMERB domains are bivalent Rab8 family effectors evolved by gene duplication

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Amrita Rai ◽  
Anastasia Oprisko ◽  
Jeremy Campos ◽  
Yangxue Fu ◽  
Timon Friese ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Gene Duplication ◽  
Binding Sites ◽  
Single Domain ◽  
Effector Protein ◽  
Rab Proteins ◽  
Endosomal Trafficking ◽  
Effector Molecules ◽  
Effector Domains ◽  
Rab Effector

In their active GTP-bound form, Rab proteins interact with proteins termed effector molecules. In this study, we have thoroughly characterized a Rab effector domain that is present in proteins of the Mical and EHBP families, both known to act in endosomal trafficking. Within our study, we show that these effectors display a preference for Rab8 family proteins (Rab8, 10, 13 and 15) and that some of the effector domains can bind two Rab proteins via separate binding sites. Structural analysis allowed us to explain the specificity towards Rab8 family members and the presence of two similar Rab binding sites that must have evolved via gene duplication. This study is the first to thoroughly characterize a Rab effector protein that contains two separate Rab binding sites within a single domain, allowing Micals and EHBPs to bind two Rabs simultaneously, thus suggesting previously unknown functions of these effector molecules in endosomal trafficking.

The metastatic cell: Behaviour and biochemistry

Cell ◽  
1991 ◽  
Vol 66 (5) ◽  
pp. 835-836 ◽  
Author(s):  
Patricia S. Steeg
Keyword(s):  
Cell Behaviour ◽  
Metastatic Cell

scholarly journals Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration

2012 ◽  
Vol 196 (2) ◽  
pp. 277-295 ◽  
Author(s):  
Elena Rainero ◽  
Patrick T. Caswell ◽  
Patricia A.J. Muller ◽  
Joan Grindlay ◽  
Mary W. McCaffrey ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Diacylglycerol Kinase ◽  
Tumor Cell Invasion ◽  
Mutant P53 ◽  
Αvβ3 Integrin ◽  
P53 Expression ◽  
Endosomal Recycling ◽  
Coupling Protein ◽  
Α5β1 Integrin ◽  
Invasive Cell

Inhibition of αvβ3 integrin or expression of oncogenic mutants of p53 promote invasive cell migration by enhancing endosomal recycling of α5β1 integrin under control of the Rab11 effector Rab-coupling protein (RCP). In this paper, we show that diacylglycerol kinase α (DGK-α), which phosphorylates diacylglycerol to phosphatidic acid (PA), was required for RCP to be mobilized to and tethered at the tips of invasive pseudopods and to allow RCP-dependent α5β1 recycling and the resulting invasiveness of tumor cells. Expression of a constitutive-active mutant of DGK-α drove RCP-dependent invasion in the absence of mutant p53 expression or αvβ3 inhibition, and conversely, an RCP mutant lacking the PA-binding C2 domain was not capable of being tethered at pseudopod tips. These data demonstrate that generation of PA downstream of DGK-α is essential to connect expression of mutant p53s or inhibition of αvβ3 to RCP and for this Rab11 effector to drive the trafficking of α5β1 that is required for tumor cell invasion through three-dimensional matrices.

scholarly journals Cellular expression of Noc2, a Rab effector protein, in endocrine and exocrine tissues in the mouse

2006 ◽  
Vol 127 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Hiroki Teramae ◽  
Wakako Fujimoto ◽  
Susumu Seino ◽  
Toshihiko Iwanaga
Keyword(s):  
Effector Protein ◽  
Cellular Expression ◽  
Rab Effector
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