# Dissection of the TORC1 Signaling Network in Yeast

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $43,414

## Abstract

SUMMARY/ABSTRACT
The Target of Rapamycin kinase Complex I (TORC1) is a master regulator of cell growth and
metabolism in eukaryotes. Work carried out over the last 20 years has shed light on the mechanisms
underlying hormone and amino acid signaling to TORC1, but it is still unclear how other key signals,
such as glucose starvation, are transmitted to this highly conserved complex. In the last grant period,
we examined TORC1 signaling in budding yeast, and found that the PKC, Gcn2, Sit4, and CK2
signaling pathways work together with the GAP SEAC (GATOR1/2 in humans) to inhibit TORC1 via the
highly-conserved GTPases, Gtr1/2 (Rag A/B and C/D in humans). This in turn releases TORC1 to
move into a single inactive body at the edge of the vacuole/lysosome—an event that depends on the
TORC1 binding protein, Pib2. Building on this framework, we now wish to: (1) Identify and characterize
the proteins and pathways work in parallel with Gtr1/2 to regulate TORC1, and (2) determine how the
conserved Gcn2, PKC, Sit4, CK2 pathways, regulate TORC1 via Gtr1/2. To address the first question,
we purified TORC1 from cells exposed to a variety of stress and starvation conditions, and identified
numerous new interactors. The most notable are the uncharacterized vacuolar/lysosomal membrane
proteins Ydl180w, Ygr125w and Syg1, since they bind tightly to TORC1 and are required for its
movement into, or out of, the inactive bodies. We now propose to study the function of these TORC1
binding proteins in detail, testing the hypotheses that: (i) Ydl180w is repressor of TORC1 and competes
with Gtr1/2 to control TORC1 activity, (ii) Ygr125w is a sulfur dependent activator of TORC1, and (iii)
Syg1 is a phosphate dependent activator of TORC1. To address the second question, we purified the
major Gtr1/2 regulator SEAC, and mapped its phosphorylation in glucose and nitrogen starvation
conditions. This led to the identification of over 150 phosphorylation sites, many of which are hyper- or
hypo-phosphorylated during glucose and/or nitrogen starvation. This grant supplement request funds
to add a URM student to the lab. The student will focus on dissecting the function of Ydl180w (now
called Ait1), examining the role that starvation dependent phosphorylation of Ait1 plays in TORC1
regulation and dissecting the role that ligand binding to Ait1 plays in regulating cell growth and
metabolism. Our proposal is innovative in that we study new and unexplored aspects of TORC1
signaling using state-of-the-art systems, proteomic, and biochemical approaches. The proposed
research is significant in that it promises to shed light on the mechanisms underlying cell growth control,
and complex signal integration, in an important model organism—with implications for (a)
understanding TORC1 related diseases such as cancer, epilepsy, diabetes and obesity, since many of
the proteins and pathways under investigation are conserved and (b) developing drugs that selectively
block the growth of pathogenic fu...

## Key facts

- **NIH application ID:** 10598274
- **Project number:** 3R01GM097329-11S1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Andrew Paul Capaldi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,414
- **Award type:** 3
- **Project period:** 2011-09-30 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598274

## Citation

> US National Institutes of Health, RePORTER application 10598274, Dissection of the TORC1 Signaling Network in Yeast (3R01GM097329-11S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10598274. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*