Small GTP-binding proteins (G proteins) exist in eukaryotes from yeast to human and constitute a superfamily consisting of more than 100 members. This superfamily is structurally classified into at least five families: the Ras, Rho, Rab, Sar1/Arf, and Ran families. They regulate a wide variety of cell functions as biological timers (biotimers) that initiate and terminate specific cell functions and determine the periods of time for the continuation of the specific cell functions. They furthermore play key roles in not only temporal but also spatial determination of specific cell functions. The Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. Many upstream regulators and downstream effectors of small G proteins have been isolated, and their modes of activation and action have gradually been elucidated. Cascades and cross-talks of small G proteins have also been clarified. In this review, functions of small G proteins and their modes of activation and action are described.

Small GTP-Binding Proteins

Mammalian Ras interacts directly with the serine/threonine kinase Raf

From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction - mainly in human cancer - is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.

RAS oncogenes: the first 30 years

Glucose and related sugars repress the transcription of genes encoding enzymes required for the utilization of alternative carbon sources; some of these genes are also repressed by other sugars such as galactose, and the process is known as catabolite repression. The different sugars produce signals which modify the conformation of certain proteins that, in turn, directly or through a regulatory cascade affect the expression of the genes subject to catabolite repression. These genes are not all controlled by a single set of regulatory proteins, but there are different circuits of repression for different groups of genes. However, the protein kinase Snf1/Cat1 is shared by the various circuits and is therefore a central element in the regulatory process. Snf1 is not operative in the presence of glucose, and preliminary evidence suggests that Snf1 is in a dephosphorylated state under these conditions. However, the enzymes that phosphorylate and dephosphorylate Snf1 have not been identified, and it is not known how the presence of glucose may affect their activity. What has been established is that Snf1 remains active in mutants lacking either the proteins Grr1/Cat80 or Hxk2 or the Glc7 complex, which functions as a protein phosphatase. One of the main roles of Snf1 is to relieve repression by the Mig1 complex, but it is also required for the operation of transcription factors such as Adr1 and possibly other factors that are still unidentified. Although our knowledge of catabolite repression is still very incomplete, it is possible in certain cases to propose a partial model of the way in which the different elements involved in catabolite repression may be integrated.

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Yeast Carbon Catabolite Repression

Yeast genes were isolated that are required for restoring the osmotic gradient across the cell membrane in response to increased external osmolarity. Two of these genes, HOG1 and PBS2, encode members of the mitogen-activated protein kinase (MAP kinase) and MAP kinase kinase gene families, respectively. MAP kinases are activated by extracellular ligands such as growth factors and function as intermediate kinases in protein phosphorylation cascades. A rapid, PBS2-dependent tyrosine phosphorylation of HOG1 protein occurred in response to increases in extracellular osmolarity. These data define a signal transduction pathway that is activated by changes in the osmolarity of the extracellular environment.

https://science.sciencemag.org/content/sci/259/5102/1760.full.pdf

An osmosensing signal transduction pathway in yeast.

https://www.cell.com/cell/pdf/0092-8674(85)90305-8.pdf

In yeast, RAS proteins are controlling elements of adenylate cyclase

Mutants of Saccharomyces cerevisiae that require cAMP for growth have been isolated. Some of the mutants isolated were deficient in adenylate cyclase activity and mapped at a locus, cyr1, located near the centromere of chromosome X. Growth of cells carrying the cyr1 mutation was arrested at the G1 phase of the yeast cell cycle in the absence of cAMP. The cyr1 mutation was suppressed by a secondary mutation designated bcy1. The bcy1 mutation bypassed the need for cAMP for growth. The bcy1 mutants had extremely low levels of cAMP-binding protein and cAMP-dependent protein kinase but produced a high level of cAMP-independent protein kinase. The results indicate that cAMP is an essential factor for yeast cells to proceed through the cell cycle via the activation of protein kinase.

https://www.pnas.org/content/pnas/79/7/2355.full.pdf

Isolation and characterization of yeast mutants deficient in adenylate cyclase and cAMP-dependent protein kinase.

Genetic analysis of the role of cAMP in yeast.

https://www.cell.com/cell/pdf/0092-8674(83)90461-0.pdf

Tatsuo Ishikawa

Papers

In yeast, RAS proteins are controlling elements of adenylate cyclase

Isolation and characterization of yeast mutants deficient in adenylate cyclase and cAMP-dependent protein kinase.

Genetic analysis of the role of cAMP in yeast.

Initiation of meiosis in yeast mutants defective in adenylate cyclase and cyclic AMP-dependent protein kinase

Control of cell division in Saccharomyces cerevisiae mutants defective in adenylate cyclase and cAMP-dependent protein kinase.