STE11 (YLR362W, UniProt P23561) curation notes

Identity

• Ste11 is the budding-yeast MEKK-family MAP kinase kinase kinase (MAP3K); 717 aa, N-terminal SAM domain
  (20-84), autoinhibitory region carrying the Ste20 phosphosites, C-terminal Ser/Thr kinase domain (415-712)
  [file:yeast/STE11/STE11-uniprot.txt "Belongs to the protein kinase superfamily. STE Ser/Thr"].
• Not to be confused with the S. pombe HMG-box transcription factor Ste11 (the S. pombe Ste11 ortholog is
  Byr2, SPBC1D7.05, which appears as an IBA donor).

Molecular function: MAP3K

• In vitro reconstitution: purified GST-Ste11 phosphorylates and activates Ste7, which phosphorylates Fus3
  PMID:8159759.
• Genetic ordering: Ste11 acts before Ste7 PMID:8455599.
• HOG branch substrate is Pbs2 PMID:16778768.
• Ste50 is also phosphorylated by Ste11 in vitro, but Ste50 is an adaptor, not a canonical output
  PMID:10397774.

Activation / regulation

• Activated by the PAK Ste20 (and Cla4 in the HOG branch), which phosphorylates the N-terminal
  autoinhibitory domain PMID:10837245;
  Cla4 redundancy in HOG PMID:16778768.
• Ste50 binds Ste11 constitutively through a heterotypic SAM-SAM interaction PMID:16337230;
  relieves N-terminal inhibition PMID:10397774.

Pathways (Ste11 is shared by three MAPK modules)

1. Pheromone response: Ste20 -> Ste11 -> Ste7 -> Fus3/Kss1, organised on the Ste5 scaffold
   [PMID:8062390 "Ste5 forms a multikinase complex that joins these kinases for efficient Fus3 activation"; PMID:7851759].
2. Filamentous / invasive growth: Ste20 -> Ste11 -> Ste7 -> Kss1 -> Ste12/Tec1
   [PMID:8259520 "in diploids some of the same kinases and STE12 are required for filamentous growth"; PMID:8001818 "the same components of the MAP kinase cascade necessary for diploid pseudohyphal development (STE20, STE11, STE7, and STE12) are also required for both filament formation and agar penetration in haploids"].
3. Sho1 branch of HOG: Sho1/Cdc42/Ste50 -> Ste11 -> Pbs2 -> Hog1
   PMID:9180081.
   Sho1 acts as adaptor bringing Ste11-Ste50 and Pbs2 together PMID:16778768.
   The ste11 single mutant is osmotolerant; ssk2/22 ste11 is not (branch redundancy).
4. Specificity: Ste5 (mating) and Sho1 (HOG) act as adaptors that pair Ste11 with Ste7 or Pbs2 respectively
   PMID:16778768.

Cell integrity / crosstalk (secondary)

• Cullen 2000: glycosylation mutants activate a Sho1 -> Ste20/Ste50 -> Ste11 -> Ste7 -> Kss1 -> Ste12 pathway;
  this is the Kss1 (filamentous growth) module, not the Pkc1-Bck1-Mkk1/2-Slt2 cascade that GO:0000196 is defined by
  PMID:10880465.
• Leng & Song 2016: Ste11-Mkk1 interaction via Nst1, proposed crosstalk to CWI PMID:26787465. Treat as non-core.

Localization

• Cytoplasmic in unstressed cells, does not enter nucleus on osmostress PMID:9755161;
  punctate relocalisation after osmostress, transient cortical recruitment via Ste50/Cdc42/Sho1 PMID:16778768.

Annotation decisions (summary)

• Core: MAPKKK activity (GO:0004709); pheromone response MAPK cascade (GO:0071507); Sho1 osmosensory
  pathway (GO:0007232) / p38MAPK (Hog1) cascade (GO:0038066); filamentous-growth signalling (GO:0001402;
  the newer GO:0062031 filamentous growth MAPK cascade names Ste11 explicitly in its definition).
• Non-core: pseudohyphal growth, invasive growth, cellular hyperosmotic response (organism-level outcomes),
  self-association.
• GO:0000196 cell integrity MAPK cascade: marked over-annotated (Ste11 is not a tier of the Slt2 cascade).
• Protein binding rows: Ste50 -> SAM domain binding; Ste5 and Sho1 -> scaffold protein binding; Fus3/Kss1 ->
  MAP kinase binding; Mkk1 -> MAP kinase kinase binding.
• PMID:8670882 (Van Aelst 1996, mammalian POR1/Rac1 paper) is the IntAct source for a Ste11 self-interaction;
  the abstract does not mention Ste11 (it was probably used as a two-hybrid control) -> UNDECIDED.