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RTK GRB2 Signaling Adaptation Module

Module rtk_grb2_signaling_adaptation 1 disorder Pathograph 5
A conserved oncology mechanism module for growth-factor and receptor tyrosine kinase (RTK) programs that signal through the GRB2 adaptor hub. Activated receptors create phosphotyrosine docking sites that recruit GRB2-containing complexes, coupling upstream RTK activity to RAS-MAPK and PI3K-AKT outputs that support proliferation, survival, and drug-adaptive fitness. The module also captures the emerging nuclear GRB2 function in RAD51-dependent replication-fork protection, linking the same adaptor control point to DNA damage response, PARP-inhibitor vulnerability, and innate immune activation when fork protection is lost.
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Pathophysiology Nodes

5
5 shared nodes are defined in this module.
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Cell Types

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No cell types are annotated for this module.
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Biological Processes

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protein autophosphorylation link INCREASED MAPK cascade link INCREASED PI3K/AKT signal transduction link INCREASED cell population proliferation link INCREASED DNA replication link DYSREGULATED DNA damage response link DYSREGULATED positive regulation of DNA repair link INCREASED DNA damage response link INCREASED innate immune response link INCREASED
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Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (for example, "rtk_grb2_signaling_adaptation#GRB2 Adaptor Hub"). The module is intended for RTK-driven cancers and signaling disorders where EGFR, ERBB2/HER2, FGFR, MET, KIT, ROS1, or related receptors converge on GRB2-mediated effector signaling. It also provides a bridge to DNA-damage and immunotherapy hypotheses when tumor-specific evidence supports GRB2-dependent replication fork protection or PARP-inhibitor/STING coupling.
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Used By Disorder Entries

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HER2-Positive Breast Cancer via Constitutive Receptor Activation → Activated RTK Phosphotyrosine Docking , GRB2 Adaptor Hub , Downstream Oncogenic Signaling → RAS-MAPK and PI3K-AKT Proliferation Output
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.
Pathograph: causal mechanism network for RTK GRB2 Signaling Adaptation Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
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Pathophysiology

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Activated RTK Phosphotyrosine Docking
trigger
Ligand binding, mutation, amplification, fusion, or autocrine stimulation activates an RTK, promoting receptor dimerization and tyrosine phosphorylation. The phosphorylated receptor tail creates docking sites for adaptor proteins and cytoplasmic substrates.
protein autophosphorylation link INCREASED
Used by disorders
HER2-Positive Breast Cancer as Constitutive Receptor Activation
Downstream
  • GRB2 Adaptor Hub Activated RTKs recruit GRB2-containing adaptor complexes at phosphotyrosine docking sites.
GRB2 Adaptor Hub
central effector
GRB2 is the adaptor control point that links phosphorylated receptors and scaffold proteins to downstream signaling complexes. In cytoplasmic RTK signaling it recruits effector complexes that activate RAS-MAPK and PI3K-AKT pathways; in stressed tumor cells, GRB2 can also participate in nuclear DNA repair and replication-fork protection.
Used by disorders
HER2-Positive Breast Cancer
Downstream
  • RAS-MAPK and PI3K-AKT Proliferation Output Cytoplasmic GRB2 adaptor complexes activate canonical RAS-MAPK and PI3K-AKT proliferative and survival signaling.
  • GRB2-Mediated Replication Fork Protection Nuclear GRB2 stabilizes RAD51 at stalled replication forks under replication stress.
RAS-MAPK and PI3K-AKT Proliferation Output
effector
GRB2-dependent adaptor signaling propagates through RAS-MAPK and PI3K-AKT pathways, increasing cell-cycle progression, proliferation, and survival. In tumors, this output can create oncogene addiction as well as adaptive bypass routes after targeted therapy.
MAPK cascade link INCREASED PI3K/AKT signal transduction link INCREASED cell population proliferation link INCREASED
Used by disorders
HER2-Positive Breast Cancer as Downstream Oncogenic Signaling
Downstream
  • GRB2 Loss PARPi-STING Vulnerability Proliferative RTK contexts can impose replication stress, making the nuclear GRB2 fork-protection branch therapeutically relevant.
GRB2-Mediated Replication Fork Protection
adaptive escape
In the nucleus, GRB2 binds RAD51 and stabilizes RAD51 at stalled replication forks, protecting reversed forks from MRE11-mediated degradation in the BRCA2-RAD51 axis. This preserves genome integrity and suppresses release of fork-derived DNA fragments into the cytoplasm.
DNA replication link DYSREGULATED DNA damage response link DYSREGULATED positive regulation of DNA repair link INCREASED
Downstream
  • GRB2 Loss PARPi-STING Vulnerability When GRB2-dependent fork protection is lost, PARP inhibition can release cytosolic DNA fragments and activate innate immune signaling.
GRB2 Loss PARPi-STING Vulnerability
therapeutic vulnerability
GRB2 depletion or functional loss under PARP inhibition releases stalled fork-derived DNA fragments into the cytoplasm, activating cGAS-STING and pro-inflammatory cytokine production. This creates a potential therapeutic vulnerability for combining GRB2 targeting, PARP inhibition, and immunotherapy in selected tumors.
DNA damage response link INCREASED innate immune response link INCREASED