# Probing a novel signaling complex that sustains AKT activation to support stress survival in cancer

> **NIH NIH F32** · CORNELL UNIVERSITY · 2022 · $67,174

## Abstract

PROJECT SUMMARY
Abnormal metabolism is a hallmark of cancer that helps cancer cells to grow, undergo malignant transformation,
and survive under stressful conditions such as nutrient deprivation. Cancer cells are exposed to many cellular
stresses during tumorigenesis, which must be overcome for the propagation of malignancy. In cancer, the
abnormal activation of many signaling networks serves to disconnect the control of growth, metabolism, and
survival, and recent efforts have sought to therapeutically target cancer metabolism. The phosphatidylinositol 3-
kinase (PI3K)-AKT (protein kinase B) signaling pathway is the most activated in human cancer and has a wide
range of effects on cellular metabolism. We have recently identified the Cdc42/Rac guanine nucleotide exchange
factor (GEF) dedicator of cytokinesis 7 (Dock7) as a novel signaling node that supports sustained basal AKT
activation and mechanistic target of rapamycin (mTOR) activity as determined by its downstream target S6
kinase (S6K) during stressful conditions to maintain signaling activity required for cell survival and transformation.
We find that Dock7 is required for multiple cancer cell lines to resist anoikis and exhibit anchorage-independent
growth. While we observe relatively low levels of AKT phosphorylation compared to stimulation by growth factors,
Dock7-dependent signaling is critical for the survival of cancer cells during nutrient deprivation. I hypothesize
that under cellular stress Dock7 serves as a scaffold for AKT, sustaining its phosphorylation and organizing
signaling partners for mTOR signaling required for stress survival. This project will investigate the role of this
novel Dock7/AKT/mTOR signaling activity in providing a survival benefit to cancer cells under cellular stress. I
propose to study the impact of Dock7-dependent signaling activity on AKT/mTOR signaling, cell survival under
stress, and critical characteristics of malignant progression and aggression. In Aim 1, I will investigate the
functional activities of the Dock-homology region 2 (DHR2) domain of Dock7, which is responsible for GEF
activity, in basal AKT phosphorylation for cancer cell stress survival and malignant transformation. In Aim 2, I
will next identify the novel role of the DHR1 domain in Dock7-dependent AKT phosphorylation, cancer cell stress
survival, and malignant transformation. Then, in Aim 3, I will identify the subcellular location of this Dock7
signaling complex under stress conditions and determine the individual roles of DHR1, DHR2, and activated
Cdc42 in Dock7 localization. The work in this proposal will provide biochemical characterization of Dock7
signaling activity that will lead to a mechanistic understanding of Dock7-dependent AKT/mTOR activation in
cancer cell stress survival. These findings will not only contribute to the understanding of cancer aggression and
metabolism but may also identify new therapeutic targets for cancer treatment.

## Key facts

- **NIH application ID:** 10536863
- **Project number:** 1F32CA275151-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Matthew R Zanotelli
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536863

## Citation

> US National Institutes of Health, RePORTER application 10536863, Probing a novel signaling complex that sustains AKT activation to support stress survival in cancer (1F32CA275151-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10536863. Licensed CC0.

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