# Characterizing oncogenic function of ITCH in melanoma

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2021 · $376,751

## Abstract

Abstract
The ITCH ubiquitin E3 ligase has been well characterized as a key molecule in immune cells. The roles of
ITCH in tumorigenesis are rather controversial due to its versatile functions in both tumor and immune cells.
Therefore, an in-depth characterization of ITCH in tumorigenesis considering both tumor and immune cells is
warranted to fill the gap in our current knowledge of ITCH’s function in cancer. We recently reported an
oncogenic function of ITCH through promoting BRAF activation in BRAF wild-type melanoma cells. Our newly
obtained preliminary results unveil a multifaceted role of ITCH in melanoma cells by modulating CRAF and
other oncogenic signals. Our results also suggest an immunosuppressive function of ITCH in the melanoma
tumor immune microenvironment. Based on these data, we hypothesize that in BRAF wild-type melanoma
cells, ITCH is a therapeutic vulnerability in both melanoma cells and the tumor immune microenvironment. In
melanoma cells, ITCH sustains oncogenic pathways including RAF-MEK-ERK and others to maintain their
fitness; activation of ITCH in immune cells, on the other hand, fosters an immunosuppressive tumor
microenvironment. Hence targeting ITCH could be a novel strategy to alter the cancer-immune set point. Three
aims are proposed to test our hypothesis. In Aim 1, we will define how K27-linked ubiquitination of RAF
proteins by ITCH modulates MEK-ERK signaling. We will characterize if ITCH facilitates the atypical
ubiquitination and subsequent activation of CRAF in a similar way to BRAF, especially in the cellular contexts
where CRAF plays a central role in activating MEK-ERK signals. Moreover, we will determine if the B55-PP2A
phosphatase functions as the reader protein for the poly-ubiquitin chains assembled on RAF proteins to
remove the inhibitory N-terminal phosphorylations. In Aim 2, we will characterize RAF-independent oncogenic
functions of ITCH. We will examine if ITCH facilitates the activation of other oncogenic pathways that fulfill its
pro-survival and pro-metastatic roles. In Aim 3, we will focus on investigating both melanoma cell-autonomous
and non-autonomous functions of ITCH in vivo. We will dissect these roles by using several mouse melanoma
models. To define if ITCH creates an immunosuppressive microenvironment, mouse syngeneic melanoma
models will be generated using Itch+/+ and Itch-/- mice, and immuno-profiling will be carried out to search for the
underlying mechanism(s). Further, Itch+/+ and Itch-/- mice will be crossed with well-characterized murine
melanoma models to assess its roles in both the tumor cell and immune microenvironment.

## Key facts

- **NIH application ID:** 10298213
- **Project number:** 1R01CA255398-01A1
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Lixin Wan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,751
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298213

## Citation

> US National Institutes of Health, RePORTER application 10298213, Characterizing oncogenic function of ITCH in melanoma (1R01CA255398-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10298213. Licensed CC0.

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