Yop1p, the Yeast Homolog of the Polyposis Locus Protein 1, Interacts with Yip1p and Negatively Regulates Cell Growth

Calero, Monica; Whittaker, Gary R.; Collins, Ruth

doi:10.1074/jbc.m008439200

Cited by 110 publications

(79 citation statements)

References 43 publications

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“…29,30 In addition, the functions of RNF11, foocen, and TB2-like 1 genes belonging to type I group are currently unknown. 31,32 On the other hand, we identified eight genes suppressed by both RET-MEN2A and RET-MEN2B mutant proteins (type IV genes). Several genes such as type I collagen, lysyl oxidase, TIMP3, and annexin I genes are down-regulated in cancer cells and have been implicated in tumor suppression.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Watanabe¹,

Ichihara²,

Hashimoto³

et al. 2002

The American Journal of Pathology

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Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A-and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-␣6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype. The RET proto-oncogene encodes a receptor tyrosine kinase with a cadherin-related motif and a cysteine-rich domain in the extracellular domain and is located on chromosome 10q11.2.1,2 It has been demonstrated that RET is a functional receptor for four related neurotrophic factors including glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin. These factors are known to require glycosylphosphatidylinositol-anchored co-receptors, GFR-␣s, as ligand-binding components and to promote the survival of various central and peripheral neurons in culture.1,2 In addition, gene knockout studies revealed that the GDNF/RET signaling plays a crucial role in the development of the enteric nervous system and the kidney. [3][4][5][6] Germline mutations of the RET gene cause dominant inherited cancer syndromes; multiple endocrine neoplasia (MEN) type 2A and 2B.7-10 MEN 2A is characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. MEN 2B shows a more complex phenotype with association of MTC, pheochromocytoma, and developmental abnormalities such as mucosal neuroma, hyperganglionosis of the intestinal tract, and marfanoid skeletal changes. The MEN2A mutations were identified in cysteine residues of the RET extracellular domain, leading to ligand-independent RET dimerization. 11,12 The MEN2B mutations were detected in methionine at codon 918 or in alanine at codon 883 in the tyrosine kinase domain and appear to activate RET without dimerization. 12,13 A variety of si...

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Section: Discussionmentioning

confidence: 99%

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Watanabe¹,

Ichihara²,

Hashimoto³

et al. 2002

The American Journal of Pathology

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“…Several yeast integral membrane proteins that appear to bind Rabs in a prenylation signal-dependent manner have been identified: Yip1p, Yop1p/ Yip2p, Yip3p, Yip4p, Yip5p, and Yif1p (7)(8)(9)55). The protein sequences and predicted topologies of Yip1p, Yip4p, and Yip5p are related, and each of these proteins has been reported to bind multiple Rabs in a prenylation signal-dependent manner (9).…”

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confidence: 99%

“…In support of this, Yip1p is associated with Yif1p, Yop1p, and Yip3p, and two-hybrid interactions have been reported between other Yip proteins (8,25,51). As a first step in exploring a potential role for yeast Yip3p in the localization of Rab proteins, we have identified the organelles where Yip3p is localized, identified proteins that are associated with Yip3p in vivo, and tested several predictions of the model that yeast Yip3p is a GDF for Rabs in vivo.…”

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Saccharomyces cerevisiae Rab-GDI Displacement Factor Ortholog Yip3p Forms Distinct Complexes with the Ypt1 Rab GTPase and the Reticulon Rtn1p

et al. 2005

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Rab GTPases are crucial regulators of organelle biogenesis, maintenance, and transport. Multiple Rabs are expressed in all cells, and each is localized to a distinct set of organelles, but little is known regarding the mechanisms by which Rabs are targeted to their resident organelles. Integral membrane proteins have been postulated to serve as receptors that recruit Rabs from the cytosol in a complex with the Rab chaperone, GDI, to facilitate the dissociation of Rab and GDI, hence facilitating loading of Rabs on membranes. We show here that the yeast (Saccharomyces cerevisiae) Golgi Rab GTPase Ypt1p can be copurified with the integral membrane protein Yip3p from detergent cell extracts. In addition, a member of the highly conserved reticulon protein family, Rtn1p, is also associated with Yip3p in vivo. However, Ypt1p did not copurify with Rtn1p, indicating that Yip3p is a component of at least two different protein complexes. Yip3p and Rtn1p are only partially colocalized in cells, with Yip3p localized predominantly to the Golgi and secondarily to the endoplasmic reticulum, whereas Rtn1p is localized predominantly to the endoplasmic reticulum and secondarily to the Golgi. Surprisingly, the intracellular localization of Rabs was not perturbed in yip3⌬ or rtn1⌬ mutants, suggesting that these proteins do not play a role in targeting Rabs to intracellular membranes. These data indicate that Yip3p may have multiple functions and that its interaction with Rabs is not critical for their recruitment to organelle membranes.

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“…Constructs were expressed at wild-type levels either in haploid cells as the only source of the Rab protein or in homozygous diploid cells where both copies were disrupted. The exceptions to the use of endogenous promoters were the Rab proteins Ypt10p and Ypt11p, which could barely be detected at endogenous levels, and the genes encoding these proteins were typically expressed under the control of P YOP1 (8). Diploids were isolated on selective medium and subsequently sporulated at 23°C.…”

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Bioinformatic and Comparative Localization of Rab Proteins Reveals Functional Insights into the Uncharacterized GTPases Ypt10p and Ypt11p

Frei

Rahl

Nussbaum

et al. 2006

Molecular and Cellular Biology

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A striking characteristic of a Rab protein is its steady-state localization to the cytosolic surface of a particular subcellular membrane. In this study, we have undertaken a combined bioinformatic and experimental approach to examine the evolutionary conservation of Rab protein localization. A comprehensive primary sequence classification shows that 10 out of the 11 Rab proteins identified in the yeast (Saccharomyces cerevisiae) genome can be grouped within a major subclass, each comprising multiple Rab orthologs from diverse species. We compared the locations of individual yeast Rab proteins with their localizations following ectopic expression in mammalian cells. Our results suggest that green fluorescent protein-tagged Rab proteins maintain localizations across large evolutionary distances and that the major known player in the Rab localization pathway, mammalian Rab-GDI, is able to function in yeast. These findings enable us to provide insight into novel gene functions and classify the uncharacterized Rab proteins Ypt10p (YBR264C) as being involved in endocytic function and Ypt11p (YNL304W) as being localized to the endoplasmic reticulum, where we demonstrate it is required for organelle inheritance.All eukaryotic cells are compartmentalized into distinct membrane-bound organelles and require tightly regulated transport of proteins and lipids between these compartments. Members of the Rab family of small GTPases are major regulators of protein and lipid traffic in the secretory and endocytic pathways (46,65). The action of Rab proteins in membrane transport was discovered with the identification of the SEC4 and YPT1 genes in yeast (Saccharomyces cerevisiae) (51, 52) and related proteins, termed Rab proteins, from mammals (10). Rab proteins comprise the most numerous subfamily of the Ras superfamily, and many are functionally uncharacterized. It is not clear whether Rab proteins regulate events that take place in the donor compartment, the vesicle or transport carrier, the acceptor compartment, or multiple locations. Also not known is whether a function(s) can be described for Rab proteins in general or whether this must be considered on a case-by-case basis. However, it is clear that Rab proteins are essential for eukaryotic cells and absolutely required for the function of all organelles connected by SNARE-mediated membrane traffic.With the completion of eukaryotic genome sequencing projects, there have been efforts to catalog the numbers of GTPase superfamily proteins. Membrane traffic in higher eukaryotes connects multiple compartments, and one reflection of this complexity may be the finding that humans have at least 60 different Rab family members (24,55,57). Other eukaryotes have fewer Rab proteins; Caenorhabditis elegans has 29 family members, Drosophila melanogaster has 26 members, and the yeast Saccharomyces cerevisiae has 11 members. As a model system, the 11 Rab proteins of the single-celled eukaryotic microbe S. cerevisiae can be considered the most minimal "membrome" (24), as other single-celle...

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Yop1p, the Yeast Homolog of the Polyposis Locus Protein 1, Interacts with Yip1p and Negatively Regulates Cell Growth

Cited by 110 publications

References 43 publications

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Saccharomyces cerevisiae Rab-GDI Displacement Factor Ortholog Yip3p Forms Distinct Complexes with the Ypt1 Rab GTPase and the Reticulon Rtn1p

Bioinformatic and Comparative Localization of Rab Proteins Reveals Functional Insights into the Uncharacterized GTPases Ypt10p and Ypt11p

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