The YIP1 family comprises an evolutionarily conserved group of membrane proteins, which share the ability to bind di-prenylated Rab proteins. The biochemical capability of YIP1 family proteins suggests a possible role in the cycle of physical localization of Rab proteins between their cognate membranes and the cytosol. YIP1 is essential for viability in yeast and a deletion of YIP1 can be rescued with the human homologue YIP1A. We have made use of this evolutionary conservation of function to generate a series of mutant alleles of YIP1 to investigate the biological role of Yip1p. Our findings indicate evidence for the participation of Yip1p in both Rab and COPII protein function; at present, we are not able to distinguish between the models that these roles represent, i.e. independent or dependent activities of Yip1p.
"In contrast to other Rab proteins
, the molecular mechanism of rab31 function is still unclear, in spite of identification of cytoskeletal participation and several interacting proteins. Immunocytochemistry analyses indicate that a large fraction of rab31 protein is localized to the perinuclear region, in the TGN and in endosomes
[Show abstract][Hide abstract] ABSTRACT: Background
Rab proteins constitute a large family of monomeric GTP-binding proteins that regulate intracellular vesicle transport. Several Rab proteins, including rab31, have been shown to affect cancer progression and are related with prognosis in various types of cancer including breast cancer. Recently, the gene encoding rab31 was found to be overexpressed in estrogen receptor-positive breast cancer tissue. In a previous study we found a significant association of high rab31 mRNA expression with poor prognosis in node-negative breast cancer patients. In the present study, we aimed to investigate the impact of rab31 (over)-expression on important aspects of tumor progression in vitro and in vivo.
Breast cancer cells displaying low (MDA-MB-231) or no (CAMA-1) endogenous rab31 expression were stably transfected with a rab31 expression plasmid. Batch-transfected cells as well as selected cell clones, expressing different levels of rab31 protein, were analyzed with regard to proliferation, cell adhesion, the invasive capacity of tumor cells, and in vivo in a xenograft tumor model. Polyclonal antibodies directed to recombinantly expressed rab31 were generated and protein expression analyzed by immunohistochemistry, Western blot analysis, and a newly developed sensitive ELISA.
Elevated rab31 protein levels were associated with enhanced proliferation of breast cancer cells. Interestingly, weak to moderate overexpression of rab31 in cell lines with no detectable endogenous rab31 expression was already sufficient to elicit distinct effects on cell proliferation. By contrast, increased expression of rab31 in breast cancer cells led to reduced adhesion towards several extracellular matrix proteins and decreased invasive capacity through MatrigelTM. Again, the rab31-mediated effects on cell adhesion and invasion were dose-dependent. Finally, in a xenograft mouse model, we observed a significantly impaired metastatic dissemination of rab31 overexpressing MDA-MB-231 breast cancer cells to the lung.
Overexpression of rab31 in breast cancer cells leads to a switch from an invasive to a proliferative phenotype as indicated by an increased cell proliferation, reduced adhesion and invasion in vitro, and a reduced capacity to form lung metastases in vivo.
Molecular Cancer 08/2012; 11(1):62. DOI:10.1186/1476-4598-11-62 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During neuron development, the biosynthetic needs of the axon initially outweigh those of dendrites. However, although a localized role for the early secretory pathway in dendrite development has been observed, such a role in axon growth remains undefined. We therefore studied the localization of Sar1, a small GTPase that controls ER export, during early stages of neuronal development that are characterized by selective and robust axon growth. At these early stages, Sar1 was selectively targeted to the axon where it gradually concentrated within varicosities in which additional proteins that function in the early secretory pathway were detected. Sar1 targeting to the axon followed axon specification and was dependent on localized actin instability. Changes in Sar1 expression levels at these early development stages modulated axon growth. Specifically, reduced expression of Sar1, which was initially only detectable in the axon, correlated with reduced axon growth, where as overexpression of Sar1 supported the growth of longer axons. In support of the former finding, expression of dominant negative Sar1 inhibited axon growth. Thus, as observed in lower organisms, mammalian cells use temporal and spatial regulation of endoplasmic reticulum exit site (ERES) to address developmental biosynthetic demands. Furthermore, axons, such as dendrites, rely on ERES targeting and assembly for growth.
[Show abstract][Hide abstract] ABSTRACT: Yip1A, a mammalian homologue of yeast Yip1p, is a multi-spanning membrane protein that is considered to be involved in transport between the endoplasmic reticulum (ER) and the Golgi. However, the precise role of Yip1A in mammalian cells remains unclear. We show here that endogenous Yip1A is localized to the ER-Golgi intermediate compartment (ERGIC). Knockdown of Yip1A by RNAi did not induce morphological changes in the Golgi, ER, or ERGIC. By analyzing a number of intracellular transport pathways, we found that Yip1A knockdown delayed the transport of Shiga toxin from the Golgi to the ER, but did not affect the anterograde transport of VSVGts045. We also found that a recombinant protein that corresponded to the N-terminal domain of Yip1A inhibited the COPI-independent retrograde transport of GFP-tagged galactosyltransferase, GT-GFP, but not the COPI-dependent retrograde transport of p58/ERGIC53. Furthermore, we found that Yip1A knockdown resulted in the dissociation of Rab6 from the membranes. These results suggested that Yip1A has a role in COPI-independent retrograde transport from the Golgi to the ER and regulates the membrane recruitment of Rab6.
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