Evidence for a functional link between profilin and CAP in the yeast S. cerevisiae

Vojtek, Anne B.; Haarer, Brian K.; Field, Jeffrey; Gerst, Jeffrey E.; Pollard, Thomas D.; Brown, Susan S.; Wigler, Michael

doi:10.1016/0092-8674(81)90013-1

Cited by 196 publications

(138 citation statements)

References 34 publications

(42 reference statements)

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“…It was shown that the N-terminal region, mapped to amino acids 1 to 168 of CAP, is required for acquirement of heat shock sensitivity in the RAS2 background, while the C-terminal region, mapped to amino acids 369 to 526, is required for normal cell morphology and respon- siveness to nutrient deprivation and excess (11). The C-terminal function appears to be related to regulation of the actin cytoskeleton, as evidenced by complementation of its function by overexpression of profilin or SNC (12,40) and by demonstration of its direct association with actin monomer and of its actin-sequestering activity (8,14). In addition, CAP possesses two proline-rich sequences in its middle region with which association of SH3 domain-containing proteins, including yeast actin-binding protein 1, was recently demonstrated (9).…”

Section: Discussionmentioning

confidence: 99%

Effect of Association with Adenylyl Cyclase-Associated Protein on the Interaction of Yeast Adenylyl Cyclase with Ras Protein

Shima

Yamawaki-Kataoka

Yanagihara

et al. 1997

Molecular and Cellular Biology

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Posttranslational modification of Ras protein has been shown to be critical for interaction with its effector molecules, including Saccharomyces cerevisiae adenylyl cyclase. However, the mechanism of its action was unknown. In this study, we used a reconstituted system with purified adenylyl cyclase and Ras proteins carrying various degrees of the modification to show that the posttranslational modification, especially the farnesylation step, is responsible for 5-to 10-fold increase in Ras-dependent activation of adenylyl cyclase activity even though it has no significant effect on their binding affinity. The stimulatory effect of farnesylation is found to depend on the association of adenylyl cyclase with 70-kDa adenylyl cyclase-associated protein (CAP), which was known to be required for proper in vivo response of adenylyl cyclase to Ras protein, by comparing the levels of Ras-dependent activation of purified adenylyl cyclase with and without bound CAP. The region of CAP required for this effect is mapped to its N-terminal segment of 168 amino acid residues, which coincides with the region required for the in vivo effect. Furthermore, the stimulatory effect is successfully reconstituted by in vitro association of CAP with the purified adenylyl cyclase molecule lacking the bound CAP. These results indicate that the association of adenylyl cyclase with CAP is responsible for the stimulatory effect of posttranslational modification of Ras on its activity and that this may be the mechanism underlying its requirement for the proper in vivo cyclic AMP response.The budding yeast Saccharomyces cerevisiae has two RAS genes, RAS1 and RAS2, whose protein products are structurally, functionally, and biochemically similar to mammalian Ras proto-oncoproteins (for reviews, see references 1 and 13). The yeast Ras proteins are essential regulatory elements of adenylyl cyclase (2, 38), which catalyzes the production of cyclic AMP (cAMP), a second messenger vital for yeast cell growth. The Ras-adenylyl cyclase pathway has been implicated in transduction of a glucose-triggered signal to an intracellular environment where a protein phosphorylation cascade is induced by cAMP. Yeast cells bearing the activated RAS2 gene, RAS2

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Section: Discussionmentioning

confidence: 99%

Effect of Association with Adenylyl Cyclase-Associated Protein on the Interaction of Yeast Adenylyl Cyclase with Ras Protein

Shima

Yamawaki-Kataoka

Yanagihara

et al. 1997

Molecular and Cellular Biology

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“…Deletion of yeast CAP results in an abnormally large cell size, random budding pattern, and abnormal actin distribution. 30,31 A CAP knockout mutant of Dictyostelium revealed aberrations in cell polarization, F-actin organization, and phototaxis. 32 Loss of Drosophila CAP results in various developmental defects and problems in maintaining oocyte polarity.…”

Section: Discussionmentioning

confidence: 99%

Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility

Yamazaki

Takamura

Masugi

et al. 2009

Laboratory Investigation

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Pancreatic cancer has the worst prognosis among cancers due to the difficulty of early diagnosis and its aggressive behavior. To characterize the aggressiveness of pancreatic cancers on gene expression, pancreatic cancer xenografts transplanted into severe combined immunodeficient mice served as a panel for gene-expression profiling. As a result of profiling, the adenylate cyclase-associated protein 1 (CAP1) gene was shown to be overexpressed in all of the xenografts. The expression of CAP1 protein in all 73 cases of pancreatic cancer was recognized by immunohistochemical analyses. The ratio of CAP1-positive tumor cells in clinical specimens was correlated with the presence of lymph node metastasis and neural invasion, and also with the poor prognosis of patients. Immunocytochemical analyses in pancreatic cancer cells demonstrated that CAP1 colocalized to the leading edge of lamellipodia with actin. Knockdown of CAP1 by RNA interference resulted in the reduction of lamellipodium formation, motility, and invasion of pancreatic cancer cells. This is the first report demonstrating the overexpression of CAP1 in pancreatic cancers and suggesting the involvement of CAP1 in the aggressive behavior of pancreatic cancer cells. Pancreatic cancer is a leading cause of cancer death worldwide. 1,2 Only about 20% of pancreatic cancer can be surgically resected with curative intent at the time of diagnosis. 3 Mainly due to the difficulty in early detection and frequent metastatic dissemination, the 5-year survival rate for pancreatic cancer patients remains below 5%. 3,4 Considering that vascular involvement, lymph node metastasis, and neural invasion have been proposed as prognostic factors, 5-7 it seems that metastasis is responsible for the aggressive behavior of pancreatic cancer. Pancreatic cancer appears to acquire genetic aberrations with successive alteration of genes involved in the regulation of cell proliferation. The alterations include activating mutations of the KRAS gene 8,9 that occur early in the stage of pancreatic carcinogenesis, and inactivations by the deletion and mutation of the CDKN2A, 10 TP53, 11 and SMAD4 genes. 12 In addition to cell proliferation, cell motility is one of the factors associated with cancer metastasis; however, no alteration of such genes has been revealed in pancreatic cancer. Therefore, alteration of the expression level of genes by epigenetic or transcriptional manner may be a cue to elucidate the mechanism of cancer metastasis.Recent developments in the technology of human genome research enabled us to obtain genome-wide gene-expression profiles, and vast numbers of marker molecule candidates for pancreatic cancer have been proposed. [13][14][15][16][17][18] In this study, xenografts of clinical specimens orthotopically transplanted into severe combined immunodeficient (SCID) mice 19 were utilized as a panel for gene-expression profiling of pancreatic cancer. Among commonly overexpressed genes in pancreatic cancer xenografts, we further evaluated the adenylate cyclaseassociated pr...

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“…7 CAP was first identified in yeast where it regulates both Ras/cAMP signaling and the actin cytoskeleton, but the Ras function is confined to yeast, accordingly, most subsequent studies have focused on its role in the actin cytoskeleton. [7][8][9][10] Mammalian CAP1 and yeast CAP both promote cofilin-driven actin filament turnover, which is believed to be a conserved feature among all CAP homologs based on the morphological phenotypes accompanying CAP perturbation, as well as the fact that expression of CAP homologs from other species rescues the actin phenotypes in CAP-knockout yeast. 7 7,15 CAP1 is more widely expressed and studied.…”

Section: Introductionmentioning

confidence: 99%

Mammalian CAP (Cyclase-associated protein) in the world of cell migration

Zhou

Zhang

Field

2013

Cell Adhesion & Migration

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Evidence for a functional link between profilin and CAP in the yeast S. cerevisiae

Cited by 196 publications

References 34 publications

Effect of Association with Adenylyl Cyclase-Associated Protein on the Interaction of Yeast Adenylyl Cyclase with Ras Protein

Effect of Association with Adenylyl Cyclase-Associated Protein on the Interaction of Yeast Adenylyl Cyclase with Ras Protein

Adenylate cyclase-associated protein 1 overexpressed in pancreatic cancers is involved in cancer cell motility

Mammalian CAP (Cyclase-associated protein) in the world of cell migration

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