Disease relevance of FAR1

• Interestingly, expression of membrane-targeted Far1p causes toxicity, most likely by activating Cdc42p uniformly at the cell cortex [1].

High impact information on FAR1

• Prior work indicates that FUS3, a member of the MAP kinase family, and FAR1, whose molecular activity is unknown, contribute to cell cycle arrest by inhibiting G1 cyclins [2].
• Mutational analysis of FAR1 reveals a correlation between its ability to associate with CDC28-CLN2 and to arrest the cell cycle [2].
• These results suggest that FAR1 protein is the link between the signaling pathway and the cell cycle machinery [2].
• FAR1 links the signal transduction pathway to the cell cycle machinery in yeast [2].
• We thus propose that FAR1 contributes to cell cycle arrest by inhibiting CLN2 [3].

Biological context of FAR1

• We have identified a gene, FAR1 (for "factor arrest"), which is necessary for cell cycle arrest but not for other responses to alpha factor: far1- mutants are insensitive to arrest despite having an intact signal transduction pathway [3].
• FAR1 is required for posttranscriptional regulation of CLN2 gene expression in response to mating pheromone [4].
• Wild-type Far1p was stable only in the G1 phase of the cell cycle [5].
• A cell sizer network involving Cln3 and Far1 controls entrance into S phase in the mitotic cycle of budding yeast [6].
• Here, we show that an increased level of the cyclin-dependent inhibitor Far1 increases cell size, whereas far1 Delta cells start bud emergence and DNA replication at a smaller size than wild type [6].

Anatomical context of FAR1

• Thus, Far1p functions as an adaptor that recruits polarity establishment proteins to the site of extracellular signaling marked by Gbetagamma to polarize assembly of the cytoskeleton in a morphogenetic gradient [7].
• Here we show that SCF(Cdc4) ubiquitylates Far1 in the nucleus, which in turn targets the multi-ubiquitylated protein to 26S proteasomes most likely located at the nuclear envelope [8].
• Using time-lapse microscopy of mating cells and artificial membrane targeting of Far1p, we show that Far1p is necessary and sufficient to recruit Cdc24p to the plasma membrane [1].

Associations of FAR1 with chemical compounds

• Cln3 Delta, far1 Delta, and strains overexpressing Far1 do not delay budding during an ethanol glucose shift-up as wild type does [6].
• In contrast, threonine 306 seems to be an important recipient of an activating modification, as substitutions at this position abolish the G1 arrest function of Far1 [9].
• A change of serine 87 to alanine prevents the cell cycle-dependent degradation of Far1, causing enhanced sensitivity to pheromone [9].

Physical interactions of FAR1

• In response to mating pheromones, a fraction of Far1 was stabilized after its export into the cytoplasm by Ste21/Msn5 [8].
• Strikingly, Bem1 also copurifies with Far1, a Fus3 substrate required for G1 arrest and proper polarized growth during mating [10].

Regulatory relationships of FAR1

• The pattern of cell cycle-regulated transcription of FAR1 could involve combinatorial control of Ste12 and Mcm1 [11].
• Fus3p is known to promote G1 arrest by activating Far1p, which inhibits three Clnp/Cdc28p kinases [12].
• Ste12 and Mcm1 regulate cell cycle-dependent transcription of FAR1 [11].
• Together, these findings indicate that Cln3 has to overcome Far1 to trigger Cln-Cdc28 activation, which then turns on SBF- and MBF-dependent transcription [6].
• Our results imply that Gbetagamma not only targets Far1p to the correct site but may also trigger a conformational change in Far1p that is required for its ability to activate Cdc24p in vivo [1].

Other interactions of FAR1

• Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2 [3].
• CLN1 overexpression had a similar effect when the FAR1 gene, encoding a negative regulator of CLN1/2 function, was deleted [13].
• The cell cycle transcription pattern for FAR1 was changed in ste12- cells: the gene was still significantly expressed in G2/M, but transcript levels were strongly reduced in G1 phase, resulting in a lack of Far1 protein accumulation [11].
• We conclude that the FAR3-dependent arrest pathway is functionally distinct from that which employs FAR1 [14].
• We find that Fus3p and Kss1p both control G1 arrest through multiple functions that operate in parallel with Far1p [12].

References