Breadcrumb

Deborah K. Morrison, Ph.D.

Deborah K. Morrison, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute

RESEARCH SUMMARY

Dr. Morrison investigates the signal transduction pathways regulated by the Ras family of GTPases. These pathways are required for normal growth and development, and mutations in various pathway components can function as disease drivers in human cancer and certain developmental disorders. Dr. Morrison has extensive expertise in the identification of protein phosphorylation sites and in the proteomic analysis of signaling complexes, which has been instrumental for her studies investigating the role of the Raf protein kinases and the KSR and CNK scaffolds in Ras-dependent signaling. Her work seeks to identify critical regulatory mechanisms that may prove helpful in the diagnosis and/or treatment of human disease states with aberrant Ras-pathway signaling.

Areas of Expertise

1) signal transduction 2) Ras GTPases 3) Raf family of protein kinases 4) protein phosphorylation 5) signaling scaffolds 6) proteomics

Publications

Selected Key Publications

Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling

Terrell EM, Durrant DE, Ritt DA, Sealover NE, Sheffels E, Spencer-Smith R, Esposito D, Zhou Y, Hancock JF, Kortum RL, Morrison DK.
Mol Cell. 76(6): 872-84, 2019. [ Journal Article ]

M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration

Kota P, Terrell EM, Ritt DA, Insinna C, Westlake CJ, Morrison DK
Proc Natl Acad Sci USA. Feb 26: 116: 3536-3545, 2019. [ Journal Article ]

Inhibition of Ras/Raf/MEK/ERK/ Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit

Ritt DA, Abreu-Blanco MT, Bindu L, Durrant DE, Zhou M, Specht SI, Stephen AG, Holderfield M, Morrison DK
Mol Cell. Dec 1: 64: 875-887, 2016. [ Journal Article ]

The CNK2 scaffold interacts with Vilse/ARHGAP39 and modulates Rac signaling during spine morphogenesis in hippocampal neurons

Lim, J., Ritt, D. A., Zhou, M., and Morrison, D. K.
Curr. Biol.. 24: 786-792, 2014. [ Journal Article ]

Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling

Freeman, A. K., Ritt, D. A., and Morrison, D. K.
Mol. Cell.. 49: 751-758, 2013. [ Journal Article ]

Job Vacancies

There are no open positions at this time. Check back again later, or take a look at CCR's Careers page.

Team

Postdoctoral Fellow (CRTA)
David Durrant, Ph.D.
Postdoctoral Fellow (Visiting)
Alice Hsu, Ph.D.
Research Biologist
Dan Ritt, M.S.
Postdoctoral Fellow (CRTA)
Russell Smith, Ph.D.
Research Biologist
Elizabeth Terrell, M.S.

Covers

Molecular Cell Cover, 2019 Dec 19;76(6):872-884

Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling

Published Date

About the Cover

The Ras and Raf family members are depicted as locks and keys, respectively. In this issue of Molecular Cell, Morrison et al. (pp. 872–884) suggest that C-Raf is the skeleton key that binds all Ras family members with high affinity, whereas B-Raf exhibits a striking preference for K-Ras. The hypervariable region (HVR) of K-Ras uniquely contains a polybasic region (PBR) that engages the B-Raf N-segment, allowing K-Ras to bind all Raf kinases with high affinity, which may contribute to its increased involvement in human cancer.  Cover art by Joe Meyer (Scientific Publications, SAIC-Frederick).

Abstract

The Ras GTPases are frequently mutated in human cancer, and, although the Raf kinases are essential effectors of Ras signaling, the tumorigenic properties of specific Ras-Raf complexes are not well characterized. Here, we examine the ability of individual Ras and Raf proteins to interact in live cells using bioluminescence resonance energy transfer (BRET) technology. We find that C-Raf binds all mutant Ras proteins with high affinity, whereas B-Raf exhibits a striking preference for mutant K-Ras. This selectivity is mediated by the acidic, N-terminal segment of B-Raf and requires the K-Ras polybasic region for high-affinity binding. In addition, we find that C-Raf is critical for mutant H-Ras-driven signaling and that events stabilizing B-Raf/C-Raf dimerization, such as Raf inhibitor treatment or certain B-Raf mutations, can allow mutant H-Ras to engage B-Raf with increased affinity to promote tumorigenesis, thus revealing a previously unappreciated role for C-Raf in potentiating B-Raf function.

Citation

Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling.  Elizabeth M Terrell 1David E Durrant 1Daniel A Ritt 1Nancy E Sealover 2Erin Sheffels 2Russell Spencer-Smith 1Dominic Esposito 3Yong Zhou 4John F Hancock 4Robert L Kortum 2Deborah K Morrison 5.   Mol. Cell, 2019 Dec 19;76(6):872-884.

Molecular Cell cover, Vol. 49, No. 4, Feb. 21, 2013

Effects of Raf dimerazation and its inhibition on normal and disease-associated Raf signaling

Published Date

About the Cover

The Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with human cancer and the related developmental disorders known as RASopathies. In this issue, Freeman et al. (pp. 751–758) demonstrate that Raf dimerization is required for normal Ras-dependent signaling as well as the function of certain disease-associated Raf mutants. A peptide inhibitor based on the Raf dimer interface, DI1 (superhero), was found to inhibit Raf dimerization (trains colliding) and Raf signaling. This study identifies the Raf dimer interface as a therapeutic target and has important implications for the treatment of human disease states with elevated Ras-Raf-MEK-ERK pathway signaling. Cover art by Allen Kane (Scientific Publications, SAIC-Frederick).

Abstract

Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with a variety of human cancers, as well as the related developmental disorders Noonan, LEOPARD, and cardiofaciocutaneous syndromes. Although the Raf kinases are known to dimerize during normal and disease-associated Raf signaling, the functional significance of Raf dimerization has not been fully elucidated. Here, using mutational analysis and a peptide inhibitor, we show that dimerization is required for normal Ras-dependent Raf activation and for the biological function of disease-associated Raf mutants with moderate, low, or impaired kinase activity. However, dimerization is not needed for the function of B-Raf mutants with high catalytic activity, such as V600E-B-Raf. Importantly, we find that a dimer interface peptide can effectively block Raf dimerization and inhibit Raf signaling when dimerization is required for Raf function, thus identifying the Raf dimer interface as a therapeutic target.

Citation

Effects of Raf dimerazation and its inhibition on normal and disease-associated Raf signaling. Freeman AK, Ritt DA, and Morrison DK. Mol Cell. 2013 Feb 21;49(4):751-8.

Science Signaling Cover, 2012 Dec 18;5(255)

A CC-SAM, for coiled coil-sterile α motif, domain targets the scaffold KSR-1 to specific sites in the plasma membrane

Published Date

About the Cover

KSR1 is a conserved component of the RAS/MAPK pathway that functions as a pseudokinase/protein scaffold.  In this issue, Koveal et al week uncovers a second domain in the scaffold KSR1 named CC-SAM that mediates plasma membrane binding. The image shows the NMR solution structure of CC-SAM, highlighting the α helix required for membrane binding. Cover image from Dorothy Koveal (Department of Molecular Biology, Cell Biology and Biochemistry, Brown University)

Abstract

Kinase suppressor of Ras-1 (KSR-1) is an essential scaffolding protein that coordinates the assembly of the mitogen-activated protein kinase (MAPK) module, consisting of the MAPK kinase kinase Raf, the MAPK kinase MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), and the MAPK ERK (extracellular signal-regulated kinase) to facilitate activation of MEK and thus ERK. Although KSR-1 is targeted to the cell membrane in part by its atypical C1 domain, which binds to phospholipids, other domains may be involved. We identified another domain in KSR-1 that we termed CC-SAM, which is composed of a coiled coil (CC) and a sterile α motif (SAM). The CC-SAM domain targeted KSR-1 to specific signaling sites at the plasma membrane in growth factor-treated cells, and it bound directly to various micelles and bicelles in vitro, indicating that the CC-SAM functioned as a membrane-binding module. By combining nuclear magnetic resonance spectroscopy and experiments in cultured cells, we found that membrane binding was mediated by helix α3 of the CC motif and that mutating residues in α3 abolished targeting of KSR-1 to the plasma membrane. Thus, in addition to the atypical C1 domain, the CC-SAM domain is required to target KSR-1 to the plasma membrane.

Citation

A CC-SAM, for coiled coil-sterile α motif, domain targets the scaffold KSR-1 to specific sites in the plasma membrane. Dorothy Koveal 1Natasha Schuh-NuhferDaniel RittRebecca PageDeborah K MorrisonWolfgang Peti. Sci Signal. 2012 Dec 18;5(255).

Genes and Development Cover, 2010 Jul 15;24(14):1496-506

The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling

Published Date

About the Cover

In this issue, Lim et al. (pp.1496-1506) report that the CNK1 scaffold interacts constitutively with the cytohesin family of ARF guanine nucleotide exchange factors, and facilitates the recruitment of the cytohesins to the cell surface in response to insulin treatment. Shown here is a stylized immunofluorescence (IF) image of insulin-treated cells, using antibodies directed against CNK1 (green) and cytohesin-2 (red), showing their colocalization (yellow) in the cytosol and at the plasma membrane. At the plasma membrane, the CNK1/cytohesin interaction promotes signaling from plasma membrane-bound Arf GTPases to the PIP5Ks to generate a PIP2-rich microenvironment that is critical for the membrane recruitment of IRS1 and signal transmission to the PI3K/AKT cascade.  Cover art by Allen Kane (Scientific Publications, SAIC-Frederick).

Abstract

Protein scaffolds play an important role in signal transduction, regulating the localization of signaling components and mediating key protein interactions. Here, we report that the major binding partners of the Connector Enhancer of KSR 1 (CNK1) scaffold are members of the cytohesin family of Arf guanine nucleotide exchange factors, and that the CNK1/cytohesin interaction is critical for activation of the PI3K/AKT cascade downstream from insulin and insulin-like growth factor 1 (IGF-1) receptors. We identified a domain located in the C-terminal region of CNK1 that interacts constitutively with the coiled-coil domain of the cytohesins, and found that CNK1 facilitates the membrane recruitment of cytohesin-2 following insulin stimulation. Moreover, through protein depletion and rescue experiments, we found that the CNK1/cytohesin interaction promotes signaling from plasma membrane-bound Arf GTPases to the phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) to generate a PIP(2)-rich microenvironment that is critical for the membrane recruitment of insulin receptor substrate 1 (IRS1) and signal transmission to the PI3K/AKT cascade. These findings identify CNK1 as a new positive regulator of insulin signaling.

Citation

The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling. Junghwa Lim 1Ming ZhouTimothy D VeenstraDeborah K Morrison. Genes Dev. 2010 Jul 15;24(14):1496-506.

J Biol Chem. Cover, 2007 Sep 7;282(36):26225-34

Caspase-dependent cleavage disrupts the ERK cascade scaffolding function of KSR1

Published Date

About the Cover

KSR1 is a protein scaffolding that facilitates ERK activation at the plasma membrane, as depicted by the colocalization of KSR1 and ERK at the cell surface (yellow in the merged image). In this issue, McKay and Morrison (pp. 26225-26234) demonstrate that caspase-dependent cleavage KSR1 in apoptotic cells disrupts the ability of KSR1 to promote ERK activation and ERK survival signaling. Pyo-tagged KSR1 staining is green, ERK staining is red, and yellow represents colocalization of the two proteins.  Cover image from Melissa McKay (NCI-Frederick).

Abstract

Kinase suppressor of Ras 1 (KSR1) is a protein scaffold that facilitates ERK cascade activation at the plasma membrane, a critical step in the signal transduction process that allows cells to respond to survival, proliferative, and differentiative cues. Here, we report that KSR1 undergoes caspase-dependent cleavage in apoptotic cells and that cleavage destroys the scaffolding function of the full-length KSR1 protein and generates a stable C-terminal fragment that can inhibit ERK activation. KSR1 is cleaved in response to multiple apoptotic stimuli and occurs in vivo during the involution of mouse mammary tissues, a morphogenic process requiring cellular apoptosis. In addition, we find that in comparison with KSR1(-/-) mouse embryonic fibroblasts expressing wild type KSR1 (WT-KSR1), cells expressing a cleavage-resistant KSR1 protein (DEVA-KSR1) exhibit reduced apoptotic signaling in response to tumor necrosis factor-alpha/cycloheximide treatment. The effect of DEVA-KSR1 expression was found to correlate with increased levels of active phosphoERK and could be significantly reversed by treating cells with the MEK inhibitor U0126. In contrast, reduced phosphoERK levels and enhanced apoptotic signaling were observed in cells constitutively expressing the C-terminal KSR1 fragment (CTF-KSR1). Moreover, we find that cleavage of WT-KSR1 correlates with a dramatic reduction in active phosphoERK levels. These findings identify KSR1 as a caspase target and suggest that cleavage of the KSR1 scaffold represents another mechanism whereby caspases down-regulate ERK survival signaling to promote cellular apoptosis.

Citation

Caspase-dependent cleavage disrupts the ERK cascade scaffolding function of KSR1. Melissa M McKay 1Deborah K Morrison. J Biol Chem. 2007 Sep 7;282(36):26225-34.