# Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases

> **NIH NIH R35** · YALE UNIVERSITY · 2024 · $770,500

## Abstract

The research proposed in this MIRA renewal application seeks to understand mechanisms of transmembrane
signaling by members of the receptor tyrosine kinase (RTK) superfamily – and other receptor-like kinases –
that do not fit the ‘rules’ that explain most RTKs. Non-canonical receptors in this group play important roles in
human disease – from neurodevelopmental disorders, to bone diseases, cancers, and congenital
malformations. The traditional model for RTK signaling involves ligand-induced receptor dimerization, which
promotes tyrosine autophosphorylation of the receptor and recruitment of downstream signaling molecules. As
we understand more about the 58 human RTKs, it has become clear that this mechanism only applies to about
half of them. For example, 10% of human RTKs are linked to WNT signaling, and must function differently
because their intracellular regions often have only catalytically inactive ‘pseudokinase’ domains. Still other
RTKs (such as ALK) have unique extracellular regions for which ligand binding and receptor regulation are
poorly understood. We have made significant progress in understanding extracellular and intracellular
structures of WNT-regulated pseudokinase RTKs. Their extracellular WNT-binding modules differ significantly
from their counterparts in proteins involved in ‘canonical’ WNT signaling, in ways that suggest well-defined
hypotheses for how these RTKs might participate as co-receptors with Frizzled receptors in b-catenin
independent WNT signaling. The intracellular pseudokinase domains of the RTKs structurally resemble the
insulin receptor kinase in its ‘inactive’ conformation, and analysis of their structural dynamics suggests that
they can undergo the same ‘inactive-like’ to ‘active-like’ conformational transitions seen for normal tyrosine
kinase domains. Indeed, we have found that these transitions can be promoted by small molecule kinase
inhibitor-like molecules, despite the fact that the isolated pseudokinase domains do not bind ATP. In the next
5-10 years of this project, we propose to test hypotheses for WNT-induced assembly of receptor complexes
that incorporate pseudokinase RTKs, elucidate their specific WNT dependence and reliance on WNT acylation,
gain high resolution structural views through crystallography and EM, and analyze their signaling properties.
We will test hypotheses for how the pseudokinase domains contribute to signaling – either by acquiring kinase
activity or by functioning as allosterically switchable interaction platforms, with precedents in other
pseudokinases and in catalytically active kinases such as Aurora A. In parallel with these efforts, we will
investigate new opportunities for therapeutic targeting of pseudokinase RTKs such as PTK7, ROR1, ROR2,
and RYK, which have all been implicated in numerous diseases. Together, these studies will provide important
new insight into signaling by receptors that do not fit normal paradigms for RTKs or WNT receptors. The new
lessons should a...

## Key facts

- **NIH application ID:** 10824253
- **Project number:** 5R35GM122485-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mark A Lemmon
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $770,500
- **Award type:** 5
- **Project period:** 2017-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824253

## Citation

> US National Institutes of Health, RePORTER application 10824253, Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases (5R35GM122485-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10824253. Licensed CC0.

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