This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, gene products, and causal edges, specialized to their tumor context. Key tumor-specific substitutions: NSCLC uses activating EGFR mutations or EML4-ALK fusion as the oncogenic driver; CML uses the BCR-ABL1 fusion kinase; GIST uses activating KIT/PDGFRA mutations; melanoma uses BRAF V600E. The complementary drug-mechanism view of RTK-proximal adaptor signaling is captured in rtk_grb2_signaling_adaptation. Key conformance target: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation".
Oncogenic Growth-Signal Lesion
trigger
A genetic or epigenetic lesion confers growth-signal autonomy. Common routes include activating mutation or amplification of a receptor tyrosine kinase (EGFR, ERBB2/HER2, KIT, PDGFRA, MET, ALK, RET), establishment of autocrine growth-factor loops in which tumor cells produce ligands for their own receptors, constitutively activating mutations in downstream transducers (KRAS/NRAS/HRAS, BRAF, PIK3CA), or inactivation of negative-feedback regulators (PTEN, NF1, the SPRY/DUSP feedback machinery). Each route uncouples mitogenic signaling from the normal requirement for extrinsic growth-factor stimulation.
Downstream
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Constitutive Mitogenic Pathway Activation
The oncogenic lesion drives ligand-independent, constitutive activation of downstream proliferative signaling cascades.
Constitutive Mitogenic Pathway Activation
central effector
The oncogenic lesion produces chronic, ligand-independent flux through the core mitogenic cascades: the RAS-RAF-MEK-ERK (MAPK) pathway driving proliferative gene expression, and the PI3K-AKT-mTOR pathway driving growth, metabolism, and survival. This sustained signal output replaces the transient, tightly regulated pulses of signaling seen in normal growth-factor responses, and is the conserved central node that disorder-specific drivers converge upon.
Downstream
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Growth-Factor-Independent Proliferation
Constitutive mitogenic signaling drives cell-cycle entry independent of external growth-factor cues.
Growth-Factor-Independent Proliferation
consequence
Sustained mitogenic signaling drives the cell through the G1 restriction point and into repeated rounds of division without the normal requirement for extrinsic growth factors. The result is autonomous, chronic proliferation, the defining phenotype of this hallmark and a foundation for tumor growth.