Signal Transduction in Blood Cells, Normal and Leukemic
Julian G. Cambronero, Ph.D.
Biochemistry & Molecular Biology
Director, Hematology Course
Boonshoft School of Medicine
Wright State University
Phone: (937) 775-3601
PubMed search: Julian Gomez-Cambronero
Karen Henkels (research associate)
Madhu Mahankali (Ph.D. student)
Lobna Elkhadragy (Ph.D. student)
Ramya Ganesan (M.S. student)
Samuel Frank (biology major)
Francis Speranza (honors thesis)
Qi (Melissa) Ye (M.S. student)
Matt Brown (M.S. student)
Brian Stodsgill (Ph.D. rotation)
Gerald Alter, Ph.D. (Wright State University, OH)
Dianne Cox, Ph.D. (Albert Einstein College of Medicine, NY)
Mary C. Dinauer, Ph.D. (Washington University in St. Louis, MO)
Joel Sawnson, Ph.D. (University of Michigan Medical School, MI)
Gregory Stahl, Ph.D. (Harvard Medical School, MA)
Douglas Joseph, Tameka Hayes, Yu-Hua Shang, Jeff Horn, Brooke Andrews, Jason Lehman, Jeff Taylor, Kara Duffy, Amy Price, George Auzani, Laurie Bromagen, Amy Dugan, Stephanie Carter, Kristina Bond, Isabel Campos, Kelly Robins, Tricia Frye, Stacy McMahon, Valerio Barauna, Mauricio Di Fulvio, Jennifer Hollyfield, Nicholas Lehman, Nick McCray, Marzena Buzanowska, Xiao Li, Farnaz Tabatabaian, Hong-Juan (Floria) Peng, Marium Husan, Kathleen Frondorf, Allissa Blystone, Kevin Daughtery, Katie Knapek, Jennalie Post, Erin Lintz, Steven Short, Terry Farkaly, Nathaniel Hatton.
Dr. Gomez-Cambronero presents workshop on
"How to Write Your First Grant"
Dr. Julian Gomez-Cambronero, chair of the Professional Development Committee of the Society for Leukocyte Biology (SLB), has organized Grant Writing Workshops at the SLB Annual Meetings in Kansas City, Mo and Maui, Hawaii. Click here to view the PowerPoint slides with lots of useful advice.
Additionally, the panelists have published a paper in Nature Immunology describing the content of the workshop, along with a compilation of tried-and-true tips. Although intended for junior investigators, the paper could also be of help for investigators at other stages. Click here to view the paper.
- News release: "Tribute Given to Dr. Gomez-Cambronero," 2005.
- News release: "WSU Researcher at the Forefront of a New Field," 2004.
- Vital Signs article: "Researchers Seek to Unravel a Central Paradigm in Cell Biology," 2004.
Summary of Research
Our laboratory studies the molecular basis of cell migration during inflammation and metastasis
Inflammation. We study the molecular basis of cell migration trying to understand what causes the abnormal behavior of highly motile cells. A class of such cells are the white blood cells (leukocytes, such as neutrophils and macrophages). In humans and other mammals, leukocytes circulating freely in the blood migrate to an open wound to defend us against an infection from germs. This is a vital and desirable function of the organism.
However, in other cases, leukocytes arrive in large numbers to the wrong place at the wrong time. Such is the case that follows a heart attack. In the condition named “ischemia-reperfusion injury,” if the blood flow is restored after the attack, then leukocytes are recruited at the heart where they can inflict great damage in healthy tissue, making the situation even worse than when it started.
- Cancer. Another aspect of cell migration that has clear and important pathological implications is in cancer metastasis. Cancer cells escape the initial tumor when the tumor reaches a certain size, becoming invasive and highly motile, and get into the systemic circulation by reaching a nearby capillary or lymph vessel. They are transported to other locations in the body to start new cancer colonies. We are applying our knowledge gained from studying leukocyte chemotaxis to the migration and tissue invasion of breast cancer cells, since in the epithelial-to-mesenchymal transition they become ameboid, free-floating and highly mobile like them.
- Inhibitors. We have discovered a variety of signaling molecules that include tyrosine kinases (JAK3 and the oncogene Fes), small GTPases (like Rac2) and lipases (phospholipase D) that are crucial for controlling the intracellular process of cell migration. Our idea is to devise ways to target those signaling pathways with specific chemical compounds (inhibitors), which could stop metastatic breast cancer cells or derail leukocytes from damaging the heart.
Signaling Pathways. At the molecular level, we are clarifying cell-signaling pathways in an ever-expanding network in which PLD2 has turned out to participate. There are protein-protein associations of PLD2 with motile proteins (Rac and WASP) or with tyrosine kinases. These signaling molecules are interdependent: if you remove the one, the other will be affected. It is very challenging to tease apart the extensive networks that are so intricately linked, but we have made important strides in elucidating these new pathways.
The targeted cell signaling molecules for current studies are: the kinases mTOR, S6K, JAK3 and oncogene product FES; the GTPases Rho and Rac2 and their GEF's; the SH2/SH3-bearing protein Grb2; WASP, actin and Arp2/3 motile proteins; and human PLD1 and PLD2.
- Techniques. Dr. Cambronero's team uses molecular and cell biology methods, such as in vitro differentiation of bone marrow progenitor cells, gene transduction, transgenic in vivo models, immunofluorescence, confocal and FRET microscopy, DNA cloning of fluorescent chimeras, analysis of gene expression by quantitative RT-PCR, site directed mutagenesis, RNA silencing and proteomics methodologies.
- Funding. Funding for Dr. Cambronero's lab is being provided by the National Institutes of Health (NIH)-National Heart Lung and Blood Institute (NHBLI); the American Heart Association (Great Rivers Chapter); American Cancer Society (ACS); Ohio board of Regents; and Boonshoft School of Medicine.
Major Research Accomplishments
- The discovery for the first time that a hematopoetic growth factor (GM-CSF) plays a key role as a chemoattractant for neutrophils involving ribosomal S6K phoshorylation. The importance is that local GM-CSF promotes wound healing (J Immunol 2003; FEBS Lett 2003).
- The discovery of new molecular cooperation in cell signaling mechanisms: Dual phosphorylation of S6K by MAPK-mTOR at separate amino acid targets (Horn et al, J Biol Chem 2003). A second messenger (phosphatidic acid, PA) that serves as a nexus for bringing together molecules of disparate activities (phospholipase PLD and kinase S6K) (Lehman et al, FASEB J 2007). We went further on discovering that PA, as a product of bacterial metabolism, is a chemoattractant for neutrophils, and we uncovered its mechanism of action (Frondorf et al, J Biol Chem 2010), explaining the advantage to leukocytes in a host-microbe immune interaction.
- The discovery for the first time that a key PLD has a previously unknown function: that of regulating leukocyte cell migration, which plays a role during the inflammatory response (Lehman et al, Blood 2006).
The uncovering of a novel regulatory molecule of PLD, Grb2, that for the first time was implicated in PLD2 signaling. Grb2 through its SH2 domain in turn binds to Sos (DiFulvio e tal, Oncogene 2006). The recognition that PLD mutants on SH2 target sites, affect DNA synthesis (J Mol Biol 2007) and PI3K/Akt mobilization (Cell Signaling 2008). The novel interaction PLD2-Grb2-Sos has been highlighted in “News and Views” Hancok, J.F. (2007) “PA promoted to Manager” Nature Cell Biol 9, 615-17 (see below).
- Our laboratory has uncovered the precise molecular mechanisms of activation of the signaling molecule PLD2 and the exact sites of interaction with other molecules. This involves its PH and PX regulatory domains, JAK3, Src, EGR tyrosine kinases and GTPases (Rac2) (Henkels et al, Mol Cell Biol 2010; Tabatabaian et al, J Biol Chem 2010; Peng et al, J Biol Chem 2011; Peng et al, Mol Cell Biol 2011). The implication of this precise regulation has bearings on leukocyte migration/inflammation. Further, we have implicated for the first time the combined action of JAK3/PLD2 on Y415 residue, that could be a novel target to inhibit cell invasion of highly metastatic breast cancer cells (Henkels et al, J Mol Biol 2011).
- We have elucidated the transcriptional regulation of lipases and kinases mTOR/S6K during differentiation of proleukemic cells discovering that mTOR keeps PLD under transcriptional repression (Tabatabaian et al, J Biol Chem 2009). Further, we have demonstrated that PLD shortens the differentiation time of cells becoming mature neutrophils. Achieving a shortened time is highly beneficial for the induction therapy of acute myelocytic leukemia patients (DiFulvio et al, J Biol Chem 2011).
- We have demonstrated how PLD recruits the motility protein “WASp” to the cell membrane accumulating in nascent phagocytic cups, its visualization and subsequent activation, which has allowed us to explain the initial molecular mechanism of phagocytosis of macrophages (Kantonen et al, Mol Cell Biol 2011).
- We have provided the groundbreaking evidence demonstrating for the first time that a phospholipase can act as a GTPase exchange factor (GEF), the first in its class (Mahankali et al, PNAS 2011), and have uncovered the catalytic site of the enzymatic activity (Mahankali et al, JOCES, 2013, Ye at el, JBC, 2013).
- American Society of Cell Biology Travel Award, Philadelphia, PA, 2010
- Biomedical Sciences Ph.D. program's Graduate Student Excellence Award 2010
- Best oral scientific presentation at the Biomedical Science Retreat, 2011
- American Society of Cell Biology Travel Award, San Francisco, CA, 2012
- Best Poster Presentation (Science Apprenticeship Program)
- The Mead Westvaco College Tuition Award
- Best Poster presentation (STREAMS Program, School of Medicine)
- Travel Award, Experimental Biology Meeting, Washington, D.C.
Mauricio Di Fulvio, Ph.D.
- Travel Award, 36th National Meeting of the Society for Leukocyte Biology, Philadelphia, PA
- Best oral presentation at the 10th Annual WSU Molecular Biology Retreat
- Award for Best Poster Presentation (WSU-BSOM, Student Day)
Jeff Horn, M.S.
- Graduate Student Excellence Award
- National Conference on Undergraduate Research (NCUR) Travel Award to Ithaca College, New York
- FETSKO Scholarship from the University Center for International Education
- Undergraduate Honors Program fellowship
A Gallery of Signaling Models
1. Model of WASp activation during leukocyte phagocytosis. WASp is activated via two alternative pathways, a PLD2-mediated pathway and a Grb2-mediated pathway. First, PLD2 catalysis of phosphatidylcholine (PC) via its two HKD lipase domains activates PI5K through PA, a product of PLD2. As a downstream product of PI5K, WASp is activated by the subsequent PIP2 produced by PI5K. Alternatively, Grb2 interacts with WASp polyprolinea through its two SH3 domains, leading to nucleation of actin filaments and to the formation of filopodia. Kantonen S, et al (2011) Mol Cell Biol 31, 4524-37.
2. GEF activity sites in PLD2 and mechanism of action. (A-B) Proposed catalytic sites of PLD2’s GEF activity according to this study. (C) Mechanism of PLD2-mediated nucleotide exchange. Key residues on PLD2, phenylalanine 129, leucine 166, phenylalanine 107 and leucine 173, are shown as part of the catalytic site that form a hydrophobic pocket. (C) Rac2 holds onto GDP with its switch I and II domains. PLD2 and Rac2 forms a complex. Mahankali M, et al (2012) J Biol Chem 287, 41417-31.
3. A switch between two enzymatic activities in the same molecule. At early times of cell stimulation both PA and Rac2-GTP are produced to begin chemotaxis. Accumulation of Rac2-GTP negatively feeds back on PLD2-lipase activity. JAK3 tyrosine kinase restores lipase activity while inhibiting GEF activity. (4) At later times, lipase predominates and GEF is further inhibited. Mahankali et al (2103) J Cell Science PMID:23378025.
4. Interplay between phosphatidic acid (PA) and Fes and JAK3 kinases with a PA sensor in breast cancer cells. MCF10A and MDA-MB-231 transfected with Fes plasmid and the EGFP-based PA sensor plasmid. Green denotes the EGFP-tagged PA sensor. Red denotes the TRITC-tagged Fes. Blue denotes DAPI staining of the nucleus. A significant increase in endogenous PA was seen co-expressing with Fes and an intracellular translocation is also detected. Ye Q, et al (2013) J Biol Chem.
5. A new JAK3-Fes-PLD2 pathway responsible for the invasive and highly proliferative phenotype of breast cancer cells. It involves two tyrosine kinases, JAK3 and oncogene Fes, as well as phospholipase D. Protein-protein interactions through SH2 motifs and activation by phosphatidic acid (PA) provide a positive activation loop between the 3 molecules, that is absent in non-transformed, normal cells. Ye Q, et al (2013) J Biol Chem.
Dr. Julian Gomez-Cambronero received his Ph.D. (cum laude) in Biochemistry/Immunology at the Complutense University (Madrid, Spain) in 1986 under Drs. M. Sanchez Crespo and J. M. Mato's direction. He then moved to the United States and completed his training in Cell Biology as a postdoctoral fellow in Dr. R. I. Sha'afi's laboratory at the Department of Physiology of the University of Connecticut Health Center, and with the late Dr. E. L. Becker. From 1991 to 1995 he was part of the faculty at the University of Connecticut, first as an Instructor and then as a Research Assistant Professor. In 1995 he moved to the Department of Physiology and Biophysics at Wright State University, chaired by Dr. P.K. Lauf, to accept a tenure-track Assistant Professorship position, and was promoted to Associate Professor in 2000 and to full Professor in 2004. He is married to Teresa Madrid and has two children, David and Julia.
Member of the graduate program
As part of the graduate faculty and as a dissertation-qualified professor, he participates in the following areas of concentration of the Biomedical Sciences Ph.D. Program: Cell Biology and Physiology, Immunology, and Biochemistry and Molecular Biology. He also participates in the Master of Science in Physiology and Neurosciences Program and the Master of Science in Microbiology and Immunology Program. His formal lectures include an "Introduction to Hematology" for first-year medical students in the team-taught Molecular, Cellular and Tissue Biology course; "Molecular Basis of Leukemia and Lymphoma" for second-year medical students; and "Signal Transduction/Molecular Endocrinology and Blood Physiology" for the Biomedical Sciences Ph.D. Program. He is course director for "Hematology" for the Boonshoft School of Medicine and was course director for "Molecular and Cellular Signaling" for the Biomedical Sciences Ph.D. Program.
Honors and awards
Dr. Cambronero is a member of the American Society for Biochemistry and Molecular Biology, the American Society of Hematology, and the Society for Leukocyte Biology. He was part of the Leukemia Society of America (LSA) Northern Connecticut Chapter Telecast in 1990; was National Finalist for the Young Investigator Award of the Society for Leukocyte Biology (SLB) in 1992; received the New Investigator Research Award from the Donaghue Medical Research Foundation in 1992; was elected as Expert Scientist by the Farmington, Connecticut, Public School Board to evaluate the science curriculum in 1994; was the subject of a biographical record in the American Men & Women of Science directory in 1995; received the Frontiers in Physiology National Research Award from the American Physiological Society (APS) in 1996; was recognized with the STARS Scholar Distinguished Service Award by The Ohio University in 1998; received the Professional Achievement "Sembrador" Award from The City of Manzanares (CR), Spain, in 2004; and received the Outstanding Achievement in Medical Education and Research Award from the Academy of Medicine of Dayton in 2007. He was named Honorary Professor at Southern Medical University, Guangzhou, China, in 2012.
Funding and scholarly publications
Dr. Cambronero has received funding from the National Institutes of Health (NIH NHLBI); the American Cancer Society (ACS); the American Heart Association (National Program); the American Physiological Society; the Ohio Board of Regents; the University of Connecticut; and Wright State University.
He was part of the NIH study sections: Erythrocyte and Leukocyte Biology (ELB), and Cell Development and Function (CDF-2). He is a permanent member of Innate Immunity and Inflammation (III) NIH Study Sections and the Molecular Signaling, Basic Cell and Molecular Biology for the American Heart Association (AHA) Research Consortium.
He has published 90 original research papers in peer-review journals (PubMed name: Gomez-Cambronero, J.), and has presented widely nationally and internationally to Research conferences and universities. He has also published science-fiction short stories and layman science-related articles in Spanish literary magazines.
Organizing a grant-writing workshop
Dr. Cambronero is the chair of the Professional Development Committee of the Society of Leukocyte Biology (SLB) whose mission is to provide educational opportunities for junior scientists and immunologists. He developed and organized the Annual Workshop on "How to Write Your First Research Grant" with advice for grad students and junior professors on grantsmanship for NIH grants, which was held in Kansas City, Mo., (September 2011) and in Maui, Hawaii (November 2012).
- Writing a First Grant Proposal — Society for Leukocyte Biology (PDF)
- “How to Write Your First Research Grant” Workshop — Society for Leukocyte Biology (PPT)
Making science available to the general public
Dr. Cambronero came up with the idea and designed el Paseo del Sistema Solar (A walk through the Solar System) in the City of Manzanares (Castilla-La Mancha, Spain). It is a scale model of the Solar System, where representations of the Sun and the planets have been positioned along a path throughout a public park, according to a scale that reduces the millions of miles in the cosmos down to yards in the park. The actual representations of the Sun and planets are spheres constructed of fiberglass, set within rectangular prisms or "monoliths" of oxidized steel, measuring about six feet tall each. The objective of the "Paseo del Sistema Solar" is for the visitor to gain an understanding and appreciation of the workings of the Solar System in a "hands-on," "walk-through" model. Dr. Cambronero wanted to make sure that science is explained and made available to the general public. He hopes this project particularly reaches the younger generations, encouraging them to become interested in the wonders of science. Visit http://www.paseodelsistemasolar.manzanares.es for more information.
Representative of Doctorate Period:
Gomez-Cambronero, J., Mato, J.M., Vivanco, F. and Sanchez-Crespo, M. (1987) Phosphorylation of partially purified 1-0-alkyl-2-lyso-glycero-3-phosphocholine: acetyl-CoA acetyltransferase from rat spleen. Biochem. J.245, 893-898. PDF
Representative of Postdoctoral Period:
Gomez-Cambronero, J., Huang, C-K., Gomez-Cambronero, T.M., Waterman, W.H., Becker, E.L. and Sha'afi, R.I. (1992) Granulocyte-macrophage colony-stimulating factor-induced protein tyrosine phosphorylation of MAP Kinase in human neutrophils. Proc. Natl. Acad. Sci.USA. 89, 7551-7555. PDF
As Principal Investigator:
Johnson, G.M. and Gomez-Cambronero, J. (1995) Priming of tyrosine phosphorylation in GM-CSF-stimulated adherent neutrophils. J. Leukocyte Biol.57, 692-698. Abstract
Gomez-Cambronero, J. (1995) Immunoprecipitation of a phospholipase D activity with anti-phosphotyrosine antibodies. J. Interferon Cytok. Res.15, 877-885. Abstract
Joseph, D., Paul, C.C., Baumann, M.A. and Gomez-Cambronero, J. (1996) S6 kinase p90rsk in GM-CSF-stimulated proliferative & mature hemopoietic cells. J. Biol. Chem.271, 13088-93. PDF
Gomez-Cambronero, J. and Veatch, C. (1996) Emerging paradigms in granulocyte macrophage colony-stimulating factor signaling. Life Sci.59, 2099-2111. Abstract
Gomez-Cambronero, J. and Keire, P. (1998) Phospholipase D: a novel major player in signal transduction. Cell Signal. 10, 387-397.
Hayes, T.S., Billington, C.J., Robinson, K.A., Sampt, E.R., Fernandez, G.A. and Gomez Cambronero, J. (1999) Binding of granulocyte-macrophage colony-stimulating factor to adherent neutrophils activates Phospholipase D. Cell Signal.11, 195-204.
Gomez-Cambronero, J. (1999) MAP kinase is activated in EGF-stimulated interphase but not in mitotic HeLa cells. FEBS Lett.443, 126-130. PDF
Grishin, A., Sinha, S., Roginskaya, V., Boyer, M.J., Gomez-Cambronero, J., Zuo, S., Kurosaki, T., Romero, G. and Corey S.J. (2000) Involvement of Shc and Cbl-PI 3 kinase in Lyn-dependent proliferative signaling pathways for G-CSF. Oncogene19, 97 105. Abstract
Andrews, B., Bond, K., Lehman, J.A., Horn, J.M., Dugan, A. and Gomez-Cambronero, J. (2000) Direct inhibition of in vitro PLD activity by 4-(2-aminoethyl) benzenesulfonyl fluoride. Biochem. Biophys. Res. Com.273, 302-311.
Paul, C.C., Aly, E., Lehman, J.A., Page, S.M., Gomez-Cambronero, J., Ackerman, S.J. and Baumann, M.A. (2000). Human cell line that differentiates to all myeloid lineages and expresses neutrophil secondary granule genes. Exp. Hematol.28, 1373-1380.
Lehman, J.A., Paul, C.C., Baumann, M.A. and Gomez-Cambronero, J. (2001) MAP kinase upregulation after hematopoietic differentiation: role of chemotaxis. Am. J. Physiol. Cell Physiol.280, 183-191. PDF
Horn, J.M., Lehman, J.A., Alter, G., Horwitz, J. and Gomez-Cambronero, J. (2001) Presence of a phospholipase D (PLD) distinct from PLD1 or PLD2 in human neutrophils: immuno-biochemical characterization and initial purification. Biochim. Biophys. Acta1530, 97-110.
Blum, J.J., Lehman, J.A., Horn, J.M. and Gomez-Cambronero, J. (2001) Phospholipase D (PLD) is present in L. donovaniand its activity increases in response to acute osmotic stress. J. Eukaryotic Microbiol.48, 102-110. Abstract
Sampt, E.R., Fernandez, G.A., Lehman, J.A., Corey, S.J., Huang, C.-K. and Gomez Cambronero, J. (2001) A systematic approach to the complete study of a signaling molecule: ribosomal p90rsk as an example.J. Biochem. Biophys. Meth.48, 219-237.
Gomez-Cambronero, J. (2001) The oxygen dissociation curve of hemoglobin: bridging the gap between Biochemistry and Physiology. J. Chem. Ed.78, 757-759. Abstract
Baumann, M.A., Paul, C.C., Lemley-Gillespie, S., Oyster, M. and Gomez-Cambronero, J. (2001) Modulation of MEK activity during G-CSF signaling alters proliferative vs.differentaitive balancing.Am. J. Hematol.68, 99-105. Abstract
Lehman, J.A. and Gomez-Cambronero, J. (2002) Molecular crosstalk between p70S6K and MAPK cell signaling pathways. Biochem. Biophys. Res. Com.293, 463-469.
Gomez-Cambronero, J., Horwitz, J. and Sha'afi, R.I. (2003) Measurements of Phospholipases A2, C and D (PLA2, PLC and PLD): in vitro microassays, analysis of enzyme isoforms and intact cells assays. Methods Mol. Biol.218, 155-1576. Abstract
Lehman, J.A., Calvo, V. and Gomez-Cambronero, J. (2003) Mechanism of ribosomal p70S6 kinase activation by GM-CSF in neutrophils: Cooperation of a MEK-related, T421/S424-kinase and a rapamycin-sensitive, mTOR-related, T389-kinase. J. Biol. Chem.278, 28130-28138. PDF
Gomez-Cambronero, J. (2003) Rapamycin inhibits GM-CSF-induced neutrophil migration. FEBS Let.550, 94-100.
Gomez-Cambronero, J., Horn, J., Paul, C.C. and Baumann, M.A. (2003) GM-CSF is a chemoattractant cytokine for neutrophils: Involvement of the ribosomal p70S6K signaling pathway. J. Immunol.171, 6846-6855. Abstract
Gomez-Cambronero, J., Frye, T. and Baumann, M.A. (2004) Ribosomal p70S6K basal activity increases upon induction of differentiation of myelomonocytic leukemic cell lines HL60, AML14 and MPD. Leukemia Res.28, 755-62.
Baumann M, Frye T, Naqvi T and Gomez-Cambronero J. (2005) Normal neutrophil maturation is associated with selective loss of MAP kinase activation by G-CSF. Leukemia Res.29, 73-8.
Di Fulvio, M. and Gomez-Cambronero, J. (2005) Phospholipase D gene expression in human neutrophils and HL-60 differentiation. J. Leukocyte Biol.77, 999-1007. Abstract
Horn, J., Miller, M. Lopez, I. and Gomez-Cambronero, J. (2005) The uncovering of a novel regulatory mechanism for PLD2: Formation of a ternary complex with Protein Tyrosine Phosphatase PTP1b and Growth Factor Receptor-Bound Protein GRB2. Biochem. Biophys. Res. Com.332, 58-67. Abstract
Di Fulvio, M., Lehman, N., Xiaohong Lin, X, Lopez, I. and Gomez-Cambronero, J. (2006) The elucidation of novel SH2 binding sites on PLD2. Oncogene 25, 3032-3040. Abstract.
Lehman N, Di Fulvio M, McCray N, Campos I, Tabatabaian F, Gomez-Cambronero J. (2006) Phagocyte cell migration is mediated by phospholipases PLD1 and PLD2. Blood108, 3564-72. Abstract.
Lehman N, Ledford B, Di Fulvio M, Frondorf K, McPhail LC, Gomez-Cambronero J. (2007) Phospholipase D2-derived phosphatidic acid binds to and activates ribosomal p70 S6 kinase independently of mTOR. FASEB J 21, 1075-1087. Abstract.
Di Fulvio M, Frondorf K, Henkels KM, Lehman N, Gomez-Cambronero J. (2007) The Grb2/PLD2 interaction is essential for lipase activity, intracellular localization and signaling in response to EGF. J Mol Biol. 367, 814-824. Abstract.
Gomez-Cambronero J, Di Fulvio M, Knapek K. (2007) Understanding phospholipase D (PLD) using leukocytes: PLD involvement in cell adhesion and chemotaxis. J Leukoc Biol. 82, 272- 281. Abstract.
Di Fulvio M, Henkels KM, Gomez-Cambronero J. (2007) Short-hairpin RNA-mediated stable silencing of Grb2 impairs cell growth and DNA synthesis. Biochem Biophys Res Commun. 357, 737-742. Abstract.
Fulvio MD, Frondorf K, Gomez-Cambronero J. (2008) Mutation of Y(179) on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner. Cell Signal. 20, 176-185. Abstract.
Lehman, N., Ledford, B., Di Fulvio, M., Frondorf, K., McPhail, L.C. and Gomez-Cambronero, J. (2007) Phospholipase D2-derived phosphatidic acid binds to and activates ribosomal p70S6 Kinase independently of mTOR. FASEB J. 21, 1075-1087.
Di Fulvio, M., Frondorf, K., Henkels, K.M., Lehman, N. and Gomez-Cambronero, J. (2007) The Grb2/PLD2 interaction is essential for lipase activity, intracellular localization and signaling in response to EGF. J. Mol. Biol. 367, 814-824.
Di Fulvio, M., Henkels, K. and Gomez-Cambronero, J. (2007) Short-hairpin RNA-mediated stable silencing of Grb2 impairs cell growth and DNA synthesis. Biochem. Biophys. Res. Commun. 357, 737-742.
Gomez-Cambronero, J. Di Fulvio, M. and Knapek, K. (2007) Understanding Phospholipase D (PLD) using leukocytes: PLD involvement in cell chemotaxis and adhesion. J. Leukocyte Biol. 82, 272-281.
Di Fulvio, M., Frondorf, K. and Gomez-Cambronero, J. (2008) Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3Kand Akt-dependent manner. Cell Signaling 20, 176-185. Information from this paper has been curated (2008) into PhosphoSite.
Haines, E., Minoo, P., Feng, Z., Resalatpanah, N., Nie, X.M., Campiglio, M., Alvarez, L., Cocolakis, E., Ridha, M., Di Fulvio, M., Gomez-Cambronero, J., Lebrun, J.J. and Ali, S. (2009) Tyrosine Phosphorylation of Grb2: Role in Prolactin/Epidermal Growth Factor Crosstalk in Mammary Epithelial Cell Growth and Differentiation. Mol. Cell. Biol. 29, 2505-2520.
Henkels, K.M., Short S., Peng, H.-J., Di Fulvio, M. and Gomez-Cambronero, J. (2009) PLD2 has both enzymatic and cell proliferation-inducing capabilities, that are differentially regulated by phosphorylation and dephosphorylation. Biochem. Biophys. Res. Commun. 389, 224-228.
Henkels, K.M., Peng, H.-J., Frondorf, K. and Gomez-Cambronero, J. (2010) A comprehensive model that explains the regulation of Phospholipase D2 (PLD2) activity by phosphorylation-dephosphorylation. Mol. Cell Biol. 30, 2251-2263.
Knapek K, Frondorf K, Post J, Short S, Cox D, Gomez-Cambronero J. (2010) The molecular basis of phospholipase D2-induced chemotaxis: elucidation of differential pathways in macrophages and fibroblasts. Mol. Cell. Biol. 30, 4492-506.
Gomez-Cambronero J. (2010) New concepts in phospholipase D signaling in inflammation and cancer. ScientificWorldJournal. 10, 1356-69
Tabatabaian F, Dougherty K, Di Fulvio M, Gomez-Cambronero J. (2010) Mammalian target of rapamycin (mTOR) and S6 kinase down-regulate phospholipase D2 basal expression and function. J. Biol. Chem. 285, 18991-9001.
Frondorf K, Henkels KM, Frohman MA, Gomez-Cambronero J. (2010) Phosphatidic acid is a leukocyte chemoattractant that acts through S6 kinase signaling. J. Biol. Chem. 285, 15837-47.
Henkels KM, Frondorf K, Gonzalez-Mejia ME, Doseff AL, Gomez-Cambronero J. (2011) IL-8-induced neutrophil chemotaxis is mediated by Janus kinase 3 (JAK3). FEBS Lett. 585, 159-66.
Peng H-J, Henkels KM, Mahankali M, Dinauer MC and Gomez-Cambronero J. (2011) Evidence for two CRIB domains in Phospholipase D2 (PLD2) that the enzyme uses to specifically bind to the small GTPase Rac2. J. Biol. Chem. 286, 16308-20.
Henkels KM, Farkaly T, Mahankali M, Segall JE and Gomez-Cambronero J. (2011) Cell Invasion of highly metastatic MTLn3 cancer cells is dependent on Phospholipase D2 (PLD2) and Janus Kinase 3 (JAK3). J. Mol. Biol. 408, 850-62.
Mahankali M, Peng H-J, Cox D and Gomez-Cambronero J. (2011) The mechanism of cell membrane ruffling relies on a Phospholipase D2 (PLD2), Grb2 and Rac2 association. Cell Signal. 23, 1291-8.
Peng J-H, Henkels KM, Mahankali M, Marchal C, Bubulya P, Dinauer MC and Gomez-Cambronero J. (2011) The dual effect of Rac2 on PLD2 regulation that explains both the onset and termination of chemotaxis. Mol. Cell. Biol. 31, 2227-40.
Gomez-Cambronero J. (2011) The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, Wasp and Rac2 (and a surprise discovery: PLD2 is a GEF). Cell Signal. 23, 1885-95.
Kantonen S, Mahankali M, Hatton N, Henkels, K, Park H, Cox, D and Gomez-Cambronero J. (2011) A novel PLD2-Grb2-WASp protein heterotrimer regulates leukocyte phagocytosis in a two-step mechanism. Mol. Cell. Biol. 31, 4524-37.
Mahankali M, Peng H-J, Henkels KM, Dinauer MC and Gomez-Cambronero J. (2011) Phospholipase D is a GTP exchange factor (GEF) for the GTPase Rac. Proc Natl Acad Sci U S A. 108, 19617-22.
Gomez-Cambronero J and Henkels K. (2012) Phospholipase D (PLD). In Encyclopedia of Signaling Molecules. Ed. by S. Choi, Springer Science LLC, New York, Chapter 17, pp. 1409-19.
Gomez-Cambronero J and Henkels K. (2012) Cloning of PLD2 from baculovirus for studies in inflammatory responses. Methods Mol. Biol. 861, 201-25.
Gomez-Cambronero J, Allen L-A H, Cathcart MK, Justment L, Kovacs EJ, McLeish KR and Nauseef WM. (2012) How to Write Your First Grant Proposal. Nature Immunology. 13, 105-8.
Di Fulvio, Frondorf K, Henkels, K, Grunwald Jr WC, Cool D and Gomez-Cambronero J. (2012) Phospholipase D2 (PLD2) shortens the time required for myeolid leukemic cell differentiation: Mechanism of action. J. Biol. Chem. 287, 393-407.
Gomez-Cambronero J. (2012) Structure analysis between the SWAP-70 RHO-GEF and the newly described PLD2-GEF. Small GTPases 3, 202-8.
Gomez-Cambronero J. (2012) Biochemical and cellular implications of a dual lipase-GEF function of phospholipase D2 (PLD2). J Leukoc. Biol. 92, 461-7.
Mahankali M, Henkels KM, Alter G, Gomez-Cambronero J. (2012) Identification of the Catalytic Site of Phospholipase D2 (PLD2) Newly Described GEF Activity. J Biol. Chem. 287, 41417-31.
Henkels KM, Mahankali M, Gomez-Cambronero J. (2013) Increased cell growth due to a new lipase-GEF (Phospholipase D2) fastly acting on Ras. Cell Signal. 25, 198-205.
Ye Q, Kantonen S, Gomez-Cambronero J. (2013) Serum Deprivation Confers the MDA-MB-231 Breast Cancer Line with an EGFR/JAK3/PLD2 System That Maximizes Cancer Cell Invasion. J Mol Biol. 425, 755-66.
Mahankali M, Henkels KM and Gomez-Cambronero J. (2013) A GEF-to-phospholipase molecular switch caused by phosphatidic acid that explains leukocyte cell migration. J. Cell Science PMID: 23378025.
Ye Q, Kantonen S, Henkels, K. and Gomez-Cambronero J. (2013) A new signaling pathway (Jak-Fes-Pld) that is enhanced in abnormal proliferation of breast cancer cells. J Biol Chem (in press)
Mahankali, Brown, M, Speranza, F and Gomez-Cambronero J. (2012) The small GTPase Rac2 downregulates gene expression of EGFR in cell adhesion J Leukocyte Biol (accepted pending minor updates)
For more information, contact:
Julian G. Cambronero, Ph.D.
064 Medical Sciences Building
Boonshoft School of Medicine
Wright State University
3640 Col. Glenn Hwy.
Dayton, OH 45435
Phone: (937) 775-3601