Mark A Lemmon, PhD, FRS

David A. Sackler Professor of Pharmacology; Co-director, Cancer Biology Institute

Research Organizations

Yale Cancer Biology Institute

Yale Cancer Center: Signal Transduction

Yale Cancer Biology Institute

Extensive Research Description

Signaling Mechanisms of Receptor Tyrosine Kinases

A major focus of the Lemmon lab is to understand transmembrane signaling by growth factor receptor tyrosine kinases (RTKs), of which there are 58 in the human proteome – separated into 20 different families. Mutations in almost all of these RTKs – some activating, some inactivating – cause cancer or other diseases, and RTKs are important therapeutic targets. We are interested in understanding how these receptors signal, and – importantly – how RTK mutations seen in afflicted patients affect receptor activity. Understanding these mutations provides an important window into molecular mechanism, but also allows us to use our mechanistic understanding to advance development and application of targeted therapeutics. To achieve this, we combine cellular, biochemical, biophysical, and structural approaches – and collaborate closely with geneticists and clinical investigators. Our goal is to link detailed mechanistic understanding to biology in the intact organism (or patient). Although we are interested in all RTKs, and in RTK signaling in general – at the organismal, cellular, and molecular levels (and use a wide variety of approaches) – we are currently focused on the following families (or groups of families) or RTKs:

1. The Epidermal Growth Factor Receptor (EGFR) family
Often considered a ‘prototypic’ RTK, the EGFR has been a major focus of our work for the past decade or so. Combining crystallographic, cellular, and other approaches we have developed a sophisticated understanding of how growth factor binding promotes dimerization of the extracellular region of the receptor, how EGFR is regulated allosterically, and how its intracellular juxtamembrane region contributes to activation. We have also defined the molecular function of the extracellular EGFR inhibitor Argos, from which we hope to extract clues for developing new EGFR inhibitory approaches in cancer.

A second key area in our EGFR work is to understand how different activating ligands can promote distinct modes of signaling through this single receptor. EGF, TGF-alpha, betacellulin, HB-EGF, epiregulin, epigen, and amphiregulin all signal through EGFR - but with subtly different consequences. Our most recent work is revealing some unexpected structural origins for these differences that are impacting how we think about the EGFR.

2. Anaplastic Lymphoma Kinase (ALK)
Working with Dr. Yaël Mossé, a pediatric oncologist at the Children’s Hospital of Philadelphia, we are trying to understand how ALK – an orphan RTK – signals. Dr. Mossé discovered in 2008 that mutations in the tyrosine kinase domain of ALK cause a significant proportion of neuroblastomas, by promoting growth factor-independent signaling by the receptor. We have worked together to understand all ALK mutations seen in neuroblastoma patients, in terms of their signaling activity and response to available ALK inhibitors that are being used in the clinic. Working with Ravi Radhakrishnan in Penn Bioengineering, we are also trying to develop algorithms for predicting whether novel ALK mutations are activating and inhibitor-sensitive, which we hope will one day guide clinical treatment. We are now extending these approaches to mutations found in EGFR in lung cancer and glioblastoma.

3. RTKs that bind Wnt Ligands
It is now known that several orphan RTKs, namely PTK7/CCK4 (called Lemon in Hydra!), Ror1/2, Ryk, and MuSK are involved in ‘non-canonical’ Wnt signaling. This is a new arena for RTKs, and how they are involved remains unclear. Moreover, PTK7/CCK4, Ror1/2 and Ryk all have so-called pseudokinases in their intracellular region. That is, they look like RTKs, but appear to have ‘dead’ tyrosine kinases. We are working hard to understand how these unusual RTKs mediate signaling by these unexpected ligands, combining biochemical, cellular and structural studies with a collaboration with Peter Klein’s lab at Penn in Xenopus and Lee Fradkin in Drosophila. This work is likely to open new paradigms in RTK signaling and – we hope – to illuminate new therapeutic avenues. We also hope that these studies will shed new light on how pseudokinases function more broadly.

Selected Publications

Full List of PubMed Publications

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Contact Info

Mark A Lemmon, PhD, FRS
Office Locations
Medical School OfficeSterling Hall of Medicine, B-Wing
333 Cedar Street, Fl 3 Rm 326A

New Haven, CT 06510
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Cancer Biology Institute OfficeWest Campus Advanced Biosciences Center
840 West Campus Drive, Fl 3 Rm 301

West Haven, CT 06516
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Mailing Address
PharmacologyDepartment of Pharmacology, Yale University School of Medicine
B326A Sterling Hall of Medicine

New Haven, CT 06520-8066