Budding yeast (S. cerevisiae) high-osmolarity (Ssk2-Pbs2-Hog1) MAPK cascade module

A decomposition of the Saccharomyces cerevisiae high-osmolarity glycerol (HOG) MAP kinase cascade, the osmostress-activated fungal realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). High external osmolarity is sensed by two functionally redundant upstream branches that converge on the single MAP2K Pbs2. In the Sln1 branch the hybrid histidine kinase Sln1 is constitutively active in the absence of stress and keeps phosphate flowing through the Hpt protein Ypd1 to the response regulator Ssk1, holding the cascade off; a drop in turgor silences Sln1, Ssk1 accumulates unphosphorylated and binds and activates the MAP3Ks Ssk2/Ssk22, so in this section of the pathway signalling output runs inversely to phosphorylation. In the Sho1 branch the tetraspan osmosensor Sho1, with the signalling mucins Msb2 and Hkr1 and the adaptor Ste50, assembles a membrane complex that brings the MAP3K Ste11 to Pbs2, which also acts as the scaffold of this branch. Pbs2 then dually phosphorylates the MAPK Hog1 on its TGY activation-loop motif. Active Hog1 translocates to the nucleus and activates transcription factors (Hot1, Msn2/Msn4, Sko1) that induce glycerol-biosynthesis and stress-response genes restoring osmotic balance. The kinase relay - Ssk2/Ssk22 -> Pbs2 -> Hog1 - is declared as an inner bundle that `conforms_to` mapk_relay, while the two osmosensing inputs and the Hog1 transcriptional output are this cascade's free extensions around the conforming core. Grounded in GO:0007231 (osmosensory signaling pathway).

This module is the Saccharomyces cerevisiae HOG-pathway realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay), and embeds two nested conforming bundles: the inner `sln1_phosphorelay` node bundles the Sln1 -> Ypd1 -> Ssk1 tiers and conforms to MODULE:two_component_relay, and the inner `hog1_relay` node bundles the Ssk2/Ssk22 -> Pbs2 -> Hog1 tiers and conforms to mapk_relay. The Sho1 branch and the downstream Hog1 transcriptional output are this cascade's free extensions around the conforming cores. Representative UniProt members (Sln1 P39928, Ypd1 Q07688, Ssk1 Q07084, Ssk2 P53599, Ssk22 P25390, Pbs2 P08018, Hog1 P32485, Sho1 P40073, Msb2 P32334, Hkr1 P41809, Ste50 P25344, Ste11 P23561) were verified against UniProt. No matching UniProt-seed PAINT IBD rows were found in the local interpro/panther cache for these S. cerevisiae exemplars, so this species-specific cascade is not assigned a PTN ancestry anchor in this pass. Signalling polarity. The Sln1 branch is a derepression circuit: Sln1 is a kinase under non-stress conditions and the continuous phosphate flow through Ypd1 to Ssk1 keeps the MAP kinase module off, so phosphorylation of the relay and output of the cascade run in opposite directions. Only unphosphorylated Ssk1 binds Ssk2/Ssk22, and efficient activation requires a dimer of unphosphorylated Ssk1, which makes the step effectively thresholded. Because Ypd1 binding shields the Ssk1 aspartyl phosphate from hydrolysis, phospho-Ssk1 is long-lived in cells, so how the relay is reset quickly enough for a rapid response is unresolved (no dedicated phospho-aspartate phosphatase is known); this is recorded as a knowledge gap rather than modelled. Branch scope. Ypd1 also delivers phosphate to the nuclear response regulator Skn7, which is not part of the canonical HOG kinase cascade but is a branch of the same multistep phosphorelay and contributes to hyperosmotic adaptation in several filamentous fungi. Skn7 is deliberately not modelled as a part here, because this module's boundary is the route from osmosensing to Hog1; the Skn7 arm belongs with its own transcriptional outputs. Species scope. The single hybrid histidine kinase Sln1 is the S. cerevisiae exception rather than the fungal rule: filamentous fungi, including the priority pathogen Aspergillus fumigatus, encode many functionally distinct hybrid histidine kinases feeding one Ypd1 hub, and the group III kinases of that expanded repertoire are the target of the phenylpyrrole fungicide fludioxonil, which is thought to act by driving a kinase-to-phosphatase transition. This module is kept S. cerevisiae-specific: the filamentous-fungal repertoire is a different architecture (many sensors, one Hpt bottleneck) and would be a separate module rather than extra members here. PANTHER grounding: kinase-tier family descriptors carry family-level PTHR ids checked against interpro/panther membership (PTHR24055 for every MAPK tier, PTHR48013 for all MAP2Ks, including MEK1/MEK2, MKK3/4/5/6/7 and Pbs2/Ste7, per the current PANTHER classification, PTHR24361 for MEKK2/MEKK3). PANTHER subfamilies are deliberately not used for those tiers: they are not clean paralog groups there (e.g. PTHR48013:SF9, named for MEK5, also contains yeast Ste7 and plant MKKs), so branch identity is carried by the representative members and the PTN evidence rather than by a subfamily id. The Ssk2/Ssk22 descriptor is the exception: both Ssk2 (P53599) and Ssk22 (P25390) are placed in PTHR48016:SF32 in the PANTHER 19.0 member index, so that subfamily is used.