# The adaptor protein Crk in immune responses

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $506,878

## Abstract

Project Summary
Natural killer (NK) cells play an important role in the human immune response to infection and malignancy.
How these cells effectively distinguish between diseased and healthy tissue is one of the key unsolved
problems in immunology today. The proposed work seeks to identify the mechanism(s) by which the small
adaptor protein CT10 regulator of kinase (Crk), and its phosphorylation, control NK cell activation and inhibition
by using both human NK cells and novel NK cell-specific conditional knockout mice. The long-term goal is to
use this knowledge and the novel imaging techniques developed herein to uncover the molecular basis of NK
cell activation and inhibition, and to develop new treatments for human primary immunodeficiency diseases
and chronic diseases such as cancer and viral infection. NK cells kill target cells through the polarized release
of lytic granules through a specialized region of cell-cell contact known as the immunological synapse (IS).
Through previous studies of the cytotoxic (Liu, D. et al., Immunity, 2009, Cover Article) and inhibitory (Liu, D.
et al., Immunity, 2012) IS, we discovered that Crk plays an essential upstream role at the IS, influencing
signaling events required for both activation and inhibition. The molecular mechanisms underlying this dual
role, however, remain unclear. We hypothesize that receptor-driven, integrin-influenced phosphorylation of
Crk acts as a molecular switch, driving a conformational change, which in turn determines Crk's ability to
interact with critical downstream signaling molecules and ultimately shapes the actin cytoskeleton into a
functional IS. Guided by strong preliminary data, we will test these hypotheses via three Specific Aims: 1)
Define the precise molecular mechanisms by which Crk-like (CrkL) protein controls NK cell activation
and inhibition. The proposed work will bring cutting-edge single molecule imaging technology to the field of
NK cell research. Experiments will determine where and when Crk is phosphorylated at the IS, as well as how
it interacts with key receptors, signaling molecules, and the actin cytoskeleton; 2) Determine the role of CrkL
in NK cells from patients with partial DiGeorge syndrome (pDGS). By studying one of the most common (1
in 3,000 births) immunodeficiency diseases, pDGS (mainly caused by CrkL haploinsufficiency), we will
determine how loss of CrkL function affects NK cell-mediated cytotoxicity; 3) Determine whether Crk or CrkL
is required for NK function in vivo. Leveraging novel NK cell-specific Crk knockout mice that we have
already generated, we will determine Crk's in vivo roles in NK cell-mediated immune responses to viral
infection and cancer, including a newly identified role in memory NK cell generation. The proposed work
involves key signaling players and regulatory mechanisms and generates a novel model system in which to
determine Crk's role as a master regulatory molecule. It is broadly relevant with direct clinical impl...

## Key facts

- **NIH application ID:** 10084254
- **Project number:** 5R01AI130197-04
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Dongfang Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $506,878
- **Award type:** 5
- **Project period:** 2018-02-13 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084254

## Citation

> US National Institutes of Health, RePORTER application 10084254, The adaptor protein Crk in immune responses (5R01AI130197-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10084254. Licensed CC0.

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