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 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

protein autophosphorylation GO:0046777 INCREASED MAPK cascade GO:0000165 INCREASED PI3K/AKT signal transduction GO:0043491 INCREASED cell population proliferation GO:0008283 INCREASED DNA replication GO:0006260 DYSREGULATED DNA damage response GO:0006974 DYSREGULATED positive regulation of DNA repair GO:0045739 INCREASED DNA damage response GO:0006974 INCREASED innate immune response GO:0045087 INCREASED

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.

Discussions and Knowledge Gaps

Which tumor states switch GRB2 from a cytoplasmic RTK adaptor role into a nuclear RAD51 replication-fork protection role, and does that switch predict combined PARP-inhibitor and immunotherapy response?

KNOWLEDGE GAP OPEN gap_grb2_cytoplasmic_nuclear_switch

Attached to: GRB2 Adaptor Hub GRB2-Mediated Replication Fork Protection

The module now captures both GRB2 signaling and DNA-repair functions, but disease entries will need tumor-specific evidence to decide whether these are parallel functions, sequential stress states, or distinct patient subtypes.

Proposed experiments: Isogenic GRB2 RTK-DDR state-switch perturbation assay

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Used By Disorder Entries

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

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Pathophysiology

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 GO:0046777 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 GO:0000165 INCREASED PI3K/AKT signal transduction GO:0043491 INCREASED cell population proliferation GO:0008283 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 GO:0006260 DYSREGULATED DNA damage response GO:0006974 DYSREGULATED positive regulation of DNA repair GO:0045739 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 GO:0006974 INCREASED innate immune response GO:0045087 INCREASED