cmfA

id: P34090
gene_symbol: cmfA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: cmfA encodes conditioned medium factor (CMF), a secreted ~80-kDa
  N- and O-glycosylated protein that functions as a cell-density (quorum) sensing
  signal during the transition from growth to multicellular development in
  Dictyostelium discoideum. When cells starve they slowly secrete CMF, and the
  extracellular concentration of CMF therefore reports the local density of
  starving cells. Starving cells must accumulate CMF above a threshold before they
  become competent to respond to pulsatile cAMP and initiate chemotactic
  aggregation; below this threshold cells do not express early developmental genes
  or differentiate into prespore and prestalk cells in response to cAMP. CMF acts
  as a ligand for cell-surface receptors (including CMFR1), and its signal is
  transduced in part through a heterotrimeric G protein that couples density
  sensing to the cAMP chemoattractant receptor cAR1, while a G protein-independent
  branch controls gene expression. Through this mechanism CMF couples cell density
  to the timing of developmental onset, synchronizing aggregation once a majority
  of cells in an area have starved.
existing_annotations:
- term:
    id: GO:0031152
    label: aggregation involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:1547939
  qualifier: acts_upstream_of_or_within
  review:
    summary: CMF is required for chemotactic aggregation during the growth-to-
      development transition. Antisense knockdown of CMF blocks aggregation, and
      exogenous purified CMF restores normal development, providing strong
      loss-of-function and rescue evidence that CMF acts upstream of aggregation.
      This captures a core biological role of the gene.
    action: ACCEPT
    reason: Directly supported by IMP evidence (antisense transformants plus
      protein-rescue) from the cloning paper. CMF is a bona fide upstream
      regulator of aggregation, so the term and qualifier are appropriate.
    supported_by:
    - reference_id: PMID:1547939
      supporting_text: CMF antisense transformants do not aggregate, whereas
        normal development is restored by the addition of purified CMF protein
    - reference_id: PMID:1547939
      supporting_text: CMF might synchronize the onset of development in
        Dictyostelium by triggering aggregation when a majority of the cells in a
        given area have starved
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:1663029
  qualifier: located_in
  review:
    summary: CMF is a secreted protein that acts in the extracellular medium as a
      diffusible density indicator. It was purified as an ~80-kDa protein from
      conditioned medium, consistent with an extracellular localization. The
      annotation is correct and reflects where the protein acts.
    action: ACCEPT
    reason: Direct biochemical evidence shows CMF is a secreted extracellular
      factor purified from conditioned medium; the located_in extracellular region
      annotation is well supported. UniProt/dictyBase also record the more
      specific extracellular space (GO:0005615), but the extracellular region
      annotation is not wrong.
    supported_by:
    - reference_id: PMID:1663029
      supporting_text: CMF is a secreted factor that functions in vivo as an
        indicator of cell density in starved cells
    - reference_id: PMID:1663029
      supporting_text: can be purified to a single 80 x 10(3) Mr band on a
        silver-stained SDS-polyacrylamide gel
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:1663029
  qualifier: involved_in
  review:
    summary: CMF is required for the density-dependent induction of early
      developmental gene expression. Below a threshold CMF concentration, starving
      cells fail to initiate expression of genes required for early development
      and do not acquire competence to induce prestalk/prespore genes in response
      to cAMP. The term is correct but general; the more specific developmental
      differentiation role is captured by GO:0045597.
    action: ACCEPT
    reason: Directly supported by IDA evidence that CMF is needed for early
      developmental gene expression. The term is fairly high-level but accurate
      for this signaling factor, which controls the developmental gene-expression
      program.
    supported_by:
    - reference_id: PMID:1663029
      supporting_text: When present below a threshold concentration, cells do not
        initiate the expression of genes required for early development
    - reference_id: PMID:1663029
      supporting_text: This factor plays an essential role in the regulatory
        pathway necessary for cells to obtain the developmental competence to
        induce prestalk and prespore gene expression in response to cAMP
- term:
    id: GO:0045597
    label: positive regulation of cell differentiation
  evidence_type: IDA
  original_reference_id: PMID:1663029
  qualifier: involved_in
  review:
    summary: CMF positively regulates differentiation into prespore and prestalk
      cells. At high cell density (high CMF), cells differentiate in response to
      cAMP; conditioned medium (containing CMF) allows low-density cells to
      differentiate, and sufficient CMF enables cells to enter the multicellular
      stage. This is a core role of CMF and is well supported.
    action: ACCEPT
    reason: Directly supported by IDA evidence that CMF is required for and
      promotes prespore/prestalk differentiation. Appropriate specific term for
      this developmental signaling factor.
    supported_by:
    - reference_id: PMID:1663029
      supporting_text: At high cell densities, the concentration of CMF is
        sufficient to enable cells to enter the multicellular stage of the
        developmental cycle
    - reference_id: PMID:1663029
      supporting_text: necessary for cells to obtain the developmental competence
        to induce prestalk and prespore gene expression in response to cAMP
references:
- id: PMID:1547939
  title: A density-sensing factor controls development in Dictyostelium.
  findings:
  - statement: CMF is an ~80-kDa glycoprotein that is slowly secreted by and
      simultaneously sensed by starved cells, mediating density-dependent
      regulation of developmental genes.
    supporting_text: This is mediated by an 80-kD glycoprotein, conditioned medium
      factor (CMF), which is slowly secreted and simultaneously sensed by starved
      cells
  - statement: CMF is required for aggregation; antisense CMF transformants fail to
      aggregate and exogenous purified CMF restores development.
    supporting_text: CMF antisense transformants do not aggregate, whereas normal
      development is restored by the addition of purified CMF protein
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified cloning paper (Jain et al. 1992, Genes Dev);
      establishes CMF sequence and its requirement for aggregation via
      antisense/rescue (source of the IMP annotation). Abstract-only in cache but
      directly supports the reviewed claims.
- id: PMID:1663029
  title: A secreted 80 x 10(3) Mr protein mediates sensing of cell density and the
    onset of development in Dictyostelium.
  findings:
  - statement: CMF is a secreted ~80-kDa protein purified from conditioned medium
      that acts as an in vivo indicator of cell density in starved cells.
    supporting_text: CMF is a secreted factor that functions in vivo as an
      indicator of cell density in starved cells
  - statement: Below a threshold CMF concentration cells fail to express early
      developmental genes; sufficient CMF enables entry into the multicellular
      stage.
    supporting_text: When present below a threshold concentration, cells do not
      initiate the expression of genes required for early development
  - statement: CMF is required for competence to induce prestalk and prespore gene
      expression in response to cAMP.
    supporting_text: necessary for cells to obtain the developmental competence to
      induce prestalk and prespore gene expression in response to cAMP
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Gomer et al. 1991, Development); biochemically
      characterizes secreted CMF and its role in density-dependent
      differentiation and gene expression (source of the three IDA annotations).
      Abstract-only in cache but supports the reviewed claims.
core_functions:
- description: CMF acts as a secreted extracellular ligand that reports starving-
    cell density (a quorum/density-sensing signal). Accumulation of secreted CMF
    above a threshold is sensed by cell-surface receptors on starved cells and,
    via downstream G protein-dependent and -independent pathways, licenses entry
    into multicellular development - promoting chemotactic aggregation and
    prespore/prestalk differentiation and inducing early developmental gene
    expression.
  molecular_function:
    id: GO:0048018
    label: receptor ligand activity
  directly_involved_in:
  - id: GO:0031152
    label: aggregation involved in sorocarp development
  - id: GO:0045597
    label: positive regulation of cell differentiation
  - id: GO:0010468
    label: regulation of gene expression
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:1547939
    supporting_text: which is slowly secreted and simultaneously sensed by starved
      cells
  - reference_id: PMID:1547939
    supporting_text: CMF antisense transformants do not aggregate, whereas normal
      development is restored by the addition of purified CMF protein
  - reference_id: PMID:1663029
    supporting_text: CMF is a secreted factor that functions in vivo as an
      indicator of cell density in starved cells