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.
Used by disorders
Ependymoma
as MYCN Amplification in Spinal Ependymoma
Downstream
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Constitutive Mitogenic Pathway Activation
The oncogenic lesion drives ligand-independent, constitutive activation of downstream proliferative signaling cascades.
Show evidence (1 reference)
"As our understanding of these details becomes increasingly sophisticated, it provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases."
Review establishing that pathogenic receptor tyrosine kinase mutations drive cancer and are a therapeutic target, supporting the oncogenic growth-signal lesion as the trigger of this module. Evidence source is OTHER because this is a review article.
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.
Used by disorders
Ependymoma
as Constitutive NF-kB Pathway Activation
Glioma
as EGFR Amplification and RTK-RAS-PI3K Mitogenic Signaling
Downstream
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Growth-Factor-Independent Proliferation
Constitutive mitogenic signaling drives cell-cycle entry independent of external growth-factor cues.
Show evidence (1 reference)
"They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis."
Hanahan & Weinberg define sustaining proliferative signaling as the first hallmark capability, the conserved central effector this module models. Evidence source is OTHER because this is a review article.
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.
Used by disorders
Ocular Melanoma
as Uveal Melanocyte Transformation and Intraocular Tumour Growth
Show evidence (1 reference)
"Recent structural studies of receptor tyrosine kinases (RTKs) have revealed unexpected diversity in the mechanisms of their activation by growth factor ligands."
Review of RTK activation by growth-factor ligands; oncogenic subversion of these activation mechanisms underlies growth-factor-independent proliferation. Evidence source is OTHER because this is a review article.