Mark A Lemmon, PhD, FRS
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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. This work is also causing us to appreciate how kinetic aspects of RTK signaling may be very important in defining signaling specificity. We are extending this concept to other receptors, including several involved in immune cell regulation that may be important in immuno-oncology.
2. Understanding activating mutations in RTKs, and how they affect inhibitor response in cancer patients
Working with ALK mutations seen in neuroblastoma patients and EGFR mutations seen in lung cancer patients, we are trying to understand how to define which new mutations seen in patients are activating - in terms of their signaling activity - and how they respond to available ALK or EGFR 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 newly identified mutations are activating and inhibitor-sensitive, which we hope will one day guide clinical treatment.
3. RTKs that bind to ligands in the Wnt family
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. 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.
Receptor tyrosine kinases
Coauthors
Research Interests
Adenocarcinoma; Biochemistry; Cell Membrane; Crystallography; Protein-Tyrosine Kinases; Receptor Aggregation; Signal Transduction; Protein Structure, Tertiary; MAP Kinase Signaling System; Protein Kinase Inhibitors; ErbB Receptors; Single Molecule Imaging; Hydrogen Deuterium Exchange-Mass Spectrometry
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Selected Publications
- Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias.Hu C, Leche CA, Kiyatkin A, Yu Z, Stayrook SE, Ferguson KM, Lemmon MA. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. Nature 2022, 602: 518-522. PMID: 35140400, PMCID: PMC8857055, DOI: 10.1038/s41586-021-04393-3.
- ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes.Shi F, Mendrola JM, Sheetz JB, Wu N, Sommer A, Speer KF, Noordermeer JN, Kan ZY, Perry K, Englander SW, Stayrook SE, Fradkin LG, Lemmon MA. ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes. Cell Reports 2021, 37: 109834. PMID: 34686333, PMCID: PMC8650758, DOI: 10.1016/j.celrep.2021.109834.
- Phosphatidylserine binding directly regulates TIM-3 function.Smith CM, Li A, Krishnamurthy N, Lemmon MA. Phosphatidylserine binding directly regulates TIM-3 function. The Biochemical Journal 2021, 478: 3331-3349. PMID: 34435619, PMCID: PMC8454703, DOI: 10.1042/BCJ20210425.
- Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases.Sheetz JB, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, Perttilä R, Preuss F, Suresh K, Stayrook SE, Tsutsui Y, Radhakrishnan R, Ungureanu D, Knapp S, Lemmon MA. Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. Molecular Cell 2020, 79: 390-405.e7. PMID: 32619402, PMCID: PMC7543951, DOI: 10.1016/j.molcel.2020.06.018.
- Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics.Kiyatkin A, van Alderwerelt van Rosenburgh IK, Klein DE, Lemmon MA. Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics. Science Signaling 2020, 13 PMID: 32817373, PMCID: PMC7521189, DOI: 10.1126/scisignal.aaz5267.
- Non-acylated Wnts Can Promote Signaling.Speer KF, Sommer A, Tajer B, Mullins MC, Klein PS, Lemmon MA. Non-acylated Wnts Can Promote Signaling. Cell Reports 2019, 26: 875-883.e5. PMID: 30673610, PMCID: PMC6429962, DOI: 10.1016/j.celrep.2018.12.104.
- EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics.Freed DM, Bessman NJ, Kiyatkin A, Salazar-Cavazos E, Byrne PO, Moore JO, Valley CC, Ferguson KM, Leahy DJ, Lidke DS, Lemmon MA. EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 2017, 171: 683-695.e18. PMID: 28988771, PMCID: PMC5650921, DOI: 10.1016/j.cell.2017.09.017.
- Dimerization of Tie2 mediated by its membrane-proximal FNIII domains.Moore JO, Lemmon MA, Ferguson KM. Dimerization of Tie2 mediated by its membrane-proximal FNIII domains. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 4382-4387. PMID: 28396397, PMCID: PMC5410832, DOI: 10.1073/pnas.1617800114.
- Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase.Emptage RP, Lemmon MA, Ferguson KM. Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase. The Biochemical Journal 2017, 474: 385-398. PMID: 27879374, PMCID: PMC5317272, DOI: 10.1042/BCJ20160792.
- Overcoming resistance to HER2 inhibitors through state-specific kinase binding.Novotny CJ, Pollari S, Park JH, Lemmon MA, Shen W, Shokat KM. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nature Chemical Biology 2016, 12: 923-930. PMID: 27595329, PMCID: PMC5069157, DOI: 10.1038/nchembio.2171.
- The Dark Side of Cell Signaling: Positive Roles for Negative Regulators.Lemmon MA, Freed DM, Schlessinger J, Kiyatkin A. The Dark Side of Cell Signaling: Positive Roles for Negative Regulators. Cell 2016, 164: 1172-1184. PMID: 26967284, PMCID: PMC4830124, DOI: 10.1016/j.cell.2016.02.047.
- The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma.Infarinato NR, Park JH, Krytska K, Ryles HT, Sano R, Szigety KM, Li Y, Zou HY, Lee NV, Smeal T, Lemmon MA, Mossé YP. The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Cancer Discovery 2016, 6: 96-107. PMID: 26554404, PMCID: PMC4707106, DOI: 10.1158/2159-8290.CD-15-1056.
- Ligand regulation of a constitutively dimeric EGF receptor.Freed DM, Alvarado D, Lemmon MA. Ligand regulation of a constitutively dimeric EGF receptor. Nature Communications 2015, 6: 7380. PMID: 26060020, PMCID: PMC4465127, DOI: 10.1038/ncomms8380.
- Comparison of Saccharomyces cerevisiae F-BAR domain structures reveals a conserved inositol phosphate binding site.Moravcevic K, Alvarado D, Schmitz KR, Kenniston JA, Mendrola JM, Ferguson KM, Lemmon MA. Comparison of Saccharomyces cerevisiae F-BAR domain structures reveals a conserved inositol phosphate binding site. Structure (London, England : 1993) 2015, 23: 352-63. PMID: 25620000, PMCID: PMC4319572, DOI: 10.1016/j.str.2014.12.009.
- ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma.Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K, Ryles H, Laudenslager M, Rappaport EF, Wood AC, McGrady PW, Hogarty MD, London WB, Radhakrishnan R, Lemmon MA, Mossé YP. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 2014, 26: 682-94. PMID: 25517749, PMCID: PMC4269829, DOI: 10.1016/j.ccell.2014.09.019.
- Complex relationship between ligand binding and dimerization in the epidermal growth factor receptor.Bessman NJ, Bagchi A, Ferguson KM, Lemmon MA. Complex relationship between ligand binding and dimerization in the epidermal growth factor receptor. Cell Reports 2014, 9: 1306-17. PMID: 25453753, PMCID: PMC4254573, DOI: 10.1016/j.celrep.2014.10.010.
- Structural basis for negative cooperativity in growth factor binding to an EGF receptor.Alvarado D, Klein DE, Lemmon MA. Structural basis for negative cooperativity in growth factor binding to an EGF receptor. Cell 2010, 142: 568-79. PMID: 20723758, PMCID: PMC2925043, DOI: 10.1016/j.cell.2010.07.015.
- Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids.Moravcevic K, Mendrola JM, Schmitz KR, Wang YH, Slochower D, Janmey PA, Lemmon MA. Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids. Cell 2010, 143: 966-77. PMID: 21145462, PMCID: PMC3031122, DOI: 10.1016/j.cell.2010.11.028.
- Cell signaling by receptor tyrosine kinases.Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010, 141: 1117-34. PMID: 20602996, PMCID: PMC2914105, DOI: 10.1016/j.cell.2010.06.011.
- ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor.Alvarado D, Klein DE, Lemmon MA. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature 2009, 461: 287-91. PMID: 19718021, PMCID: PMC2762480, DOI: 10.1038/nature08297.
- Structural basis for EGFR ligand sequestration by Argos.Klein DE, Stayrook SE, Shi F, Narayan K, Lemmon MA. Structural basis for EGFR ligand sequestration by Argos. Nature 2008, 453: 1271-5. PMID: 18500331, PMCID: PMC2526102, DOI: 10.1038/nature06978.