PHOSPHOINOSITIDE

SIGNALING PATHWAYS IN CANCER   

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ACCEPTING APPLICATIONS FOR POSTDOCTORAL POSITION

RESEARCH

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VISION & FOCUS

The major goal of the Emerling lab is to understand the role of phosphoinositide kinases, in particular the phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks), in tumor cell growth and metabolism. Our recent studies, based on gene deletion in mice, reveal that these enzymes control glucose homeostasis, insulin sensitivity and susceptibility to tumor formation in p53 mutant backgrounds, raising the possibility that inhibitors of these ‘druggable’ enzymes could be efficacious in treating cancer, in particular p53 mutant cancers.   Our work proposes to understand the biochemical basis for the function of these enzymes and to further validate them as targets for pharmaceutical intervention in cancer.

BREAST CANCER

Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancers. Women with TNBC are three times more likely to experience death compared to other subtypes. Mutations in the tumor suppressor gene TP53 (encoding p53) are found in the vast majority of TNBC. Although TP53 mutations are found frequently in TNBC, it is difficult to target p53-deficiency with drugs. The poor prognosis of TNBC can be attributed to the lack of effective targeted therapy. We have shown that the PI5P4K enzymes are crucial for the growth of breast cancers that have genetic aberrations in p53. Using preclinical studies in novel genetically engineered breast cancer mouse models and in human breast cancer cells we are investigating whether targeting these enzymes will be an effective therapy for TP53 mutant breast cancers, especially the TNBC subgroup where targeted therapies have not been effective.

METABOLISM

The bulk of cellular PI-4,5-P2 is generated at the plasma membrane by the canonical pathway in which a 5-kinase (PI4P5K) converts PI-4-P to PI-4,5-P2. The PI5P4K enzymes provide an alternative pathway for generating PI-4,5-P2 at intracellular locations, such as  the nucleus, lysosomes and autophagosomes, by phosphorylating PI-5-P. We have demonstrated that the PI5P4K enzymes play critical roles in mediating changes in metabolism in response to cellular stress. Our working model is that the PI5P4K pathway is a stress response pathway that is necessary for the maintenance of glucose metabolism, autophagy, and transcription under conditions of severe stress or upon loss of TP53. Current aims in the Emerling lab are to dissect the role(s) of the PI5P4K enzymes in these metabolic signaling pathways. 

 

MEET THE EMERLING LAB TEAM

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BROOKE M. EMERLING
RYAN LOUGHRAN

Graduate Student

Ryan recieved his BS in Biology from the University of Pittsburgh. Before joining the Emerling lab in 2016, Ryan was a research technician in the Cantley Lab at Weill Cornell Medicine. As a graduate student in the Emerling lab, he is currently focusing on uncovering the mechanism by which the PI5P4K enzymes act as compensatory metabolic sensors in p53 mutant cancers. In his spare time, he enjoys golf, tennis, and attempting to write the next Hugo award winning sci-fi novel.

 

ARCHNA RAVI

Postdoctoral Fellow

Archna received her MS in Molecular Biology from the University of Madras (2008) and her Ph.D. from National University of Singapore (2013) where she worked on RhoGTPase signaling in cell migration. Before joining the Emerling Lab in 2017, she was a postdoc at UC Irvine. Archna's research interests include understanding how the PI5P4K enzymes regulate intricate aspects of cell biology and their role(s) in metabolism and cancer. Outside the lab, Archna enjoys books, beaches, and traveling. 

LAVINIA PALAMIUC

Postdoctoral Fellow

Lavinia received her master's degree in Biotechnology from the University of Iasi, Romania (2010) and her PhD in Neuroscience from the University of Strasbourg, France (2014). Her PhD research focused on pre-symptomatic metabolic alterations in muscle tissue in a mouse model for amyotrophic lateral sclerosis. Before joining the Emerling Lab, she was a post-doc at The Scripps Research Institute where she studied fat metabolism and neuroendocrine signaling in C.elegans in Dr. Srinivasan's lab. Currently she is studying the role of PI5P4K enzymes in metabolic homeostasis and pathology. In her free time, Lavinia enjoys reading, photography, learning new languages, and hiking.

VIVIAN TIEU

Undergraduate Student

Vivian is currently a student at UC San Diego and on track to receive her BS in Human Biology in June 2020.  As an aspiring pre-med, she joined the Emerling Lab with hopes in gaining more insight on the variety of facets of medicine. During her free time, Vivian enjoys reading, biking, and exploring new “foodie” places. 

SARAH FORTE

Administrative Assistant

Sarah received her BA in Business Marketing from San Diego State University and a  Bachelor of Science in Business Administration from the University of Phoenix. Prior to joining SBP she was a Marketing Manager at the Institute for Health Maintenance.  Sarah was born and raised in Southern California. She spends most of her free time with her 2-year-old daughter and husband enjoying all that San Diego as to offer. She is a certificated Pilates instructor and continues to practice Pilates today.

LAB ALUMNI

Ann Pham (Research Associate, 2017-2018) - Currently: Research Associate, Organovo Holdings, Inc.

Oscar Donosa (Undergraduate student, 2017) - Currently: UCSD undergraduate 

 

PUBLICATIONS & REVIEWS

PSMA brings new flavors to PI3K signaling: A role for glutamate in prostate cancer

December 08, 2018

In this issue of JEM, Kaittanis et al. (https://doi.org/10.1084/jem.20171052) report a new signaling role for prostate-specific membrane antigen (PSMA), providing a mechanistic link between two major oncogenic pathways, as well as promising therapeutic implications for the diagnosis and treatment of prostate cancer.

Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy

May 03, 2018

While the majority of phosphatidylinositol-4, 5-bi- sphosphate (PI-4, 5-P2) in mammalian cells is gener- ated by the conversion of phosphatidylinositol- 4-phosphate (PI-4-P) to PI-4, 5-P2, a small fraction can be made by phosphorylating phosphatidylinosi- tol-5-phosphate (PI-5-P). The physiological rele- vance of this second pathway is not clear. Here, we show that deletion of the genes encoding the two most active enzymes in this pathway, Pip4k2a and Pip4k2b, in the liver of mice causes a large enrich- ment in lipid droplets and in autophagic vesicles during fasting. These changes are due to a defect in the clearance of autophagosomes that halts auto- phagy and reduces the supply of nutrients salvaged through this pathway. Similar defects in autophagy are seen in nutrient-starved Pip4k2a/Pip4k2b/ mouse embryonic fibroblasts and in C. elegans lack- ing the PI5P4K ortholog. These results suggest that this alternative pathway for PI-4, 5-P2 synthesis evolved, in part, to enhance the ability of multicellular organisms to survive starvation.

PIP-ing Lipids on Membranes: PTEN Takes the Cake

November 02, 2017

In this issue of Molecular Cell, Malek et al. (2017) describe a novel HPLC-MS method permitting separation of PI(3,4)P2 and PI(4,5)P2, a technical issue hindering the phosphoinositide signaling field. They use this method to uncover a new target and critical role for PTEN in cancer.

Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system.

June 16, 2016

Type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate. Mammals have three enzymes PI5P4Kα, PI5P4Kβ, and PI5P4Kγ, and these enzymes have been implicated in metabolic control, growth control, and a variety of stress responses. Here, we show that mice with germline deletion of type 2 phosphatidylinositol-5-phosphate 4-kinase gamma (Pip4k2c), the gene encoding PI5P4Kγ, appear normal in regard to growth and viability but have increased inflammation and T-cell activation as they age. Immune cell infiltrates increased in Pip4k2c(-/-) mouse tissues. Also, there was an increase in proinflammatory cytokines, including IFNγ, interleukin 12, and interleukin 2 in plasma of Pip4k2c(-/-) mice. Pip4k2c(-/-) mice had an increase in T-helper-cell populations and a decrease in regulatory T-cell populations with increased proliferation of T cells. Interestingly, mammalian target of rapamycin complex 1 (mTORC1) signaling was hyperactivated in several tissues from Pip4k2c(-/-) mice and treating Pip4k2c(-/-) mice with rapamycin reduced the inflammatory phenotype, resulting in a decrease in mTORC1 signaling in tissues and a decrease in proinflammatory cytokines in plasma. These results indicate that PI5P4Kγ plays a role in the regulation of the immune system via mTORC1 signaling.

The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis

January 07, 2016

While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kβ, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kβ preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kβ is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kβ is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kβ. The critical role of the GTP-sensing activity of PI5P4Kβ in cancer signifies this lipid kinase as a cancer therapeutic target.

Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53-Null Tumors

November 07, 2013

Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or β (PI5P4Kα and β) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and β in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K β and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A−/−, PIP4K2B+/−, and TP53−/− mice were viable and had a dramatic reduction in tumor formation compared to TP53−/−littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.

A homogeneous, high-throughput assay for phosphatidylinositol 5-phosphate 4-kinase with a novel, rapid substrate preparation.

January 10, 2013

Phosphoinositide kinases regulate diverse cellular functions and are important targets for therapeutic development for diseases, such as diabetes and cancer. Preparation of the lipid substrate is crucial for the development of a robust and miniaturizable lipid kinase assay. Enzymatic assays for phosphoinositide kinases often use lipid substrates prepared from lyophilized lipid preparations by sonication, which result in variability in the liposome size from preparation to preparation. Herein, we report a homogeneous 1536-well luciferase-coupled bioluminescence assay for PI5P4Kα. The substrate preparation is novel and allows the rapid production of a DMSO-containing substrate solution without the need for lengthy liposome preparation protocols, thus enabling the scale-up of this traditionally difficult type of assay. The Z'-factor value was greater than 0.7 for the PI5P4Kα assay, indicating its suitability for high-throughput screening applications. Tyrphostin AG-82 had been identified as an inhibitor of PI5P4Kα by assessing the degree of phospho transfer of γ-(32)P-ATP to PI5P; its inhibitory activity against PI5P4Kα was confirmed in the present miniaturized assay. From a pilot screen of a library of bioactive compounds, another tyrphostin, I-OMe tyrphostin AG-538 (I-OMe-AG-538), was identified as an ATP-competitive inhibitor of PI5P4Kα with an IC(50) of 1 µM, affirming the suitability of the assay for inhibitor discovery campaigns. This homogeneous assay may apply to other lipid kinases and should help in the identification of leads for this class of enzymes by enabling high-throughput screening efforts.

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CONTACT

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Tel: 858-646-3100
10901 North Torrey Pines Road
La Jolla, CA 92037

Principal Investigator

Brooke received her BA from the University of California, Santa Cruz and her Ph.D. from Northwestern University. As a Ph.D. student in the laboratory of Navdeep Chandel, Brooke identified and characterized novel signaling pathways that regulate the transcription factor hypoxia inducible factor-1. Upon completion of her Ph.D, Brooke joined the laboratory of Lewis Cantley at Harvard Medical School. There she discovered that the loss of function of the PI5P4Ks resulted in synthetic lethality with p53 loss and began to elucidate the role of the PI5P4K family of enzymes in cancer metabolism. After she completed her postdoctoral fellowship at Harvard Medical School, Brooke became an Instructor of Cancer Biology in Medicine at Weill Cornell Medicine where she continued her research on lipid kinase signaling and cancer metabolism. In August 2016, Brooke joined the faculty at SBP Medical Discovery Institute as an Assistant Professor in the Cancer Metabolism and Signaling Networks Program.

ELIZABETH “LIBBY” DANIELE

Laboratory Manager

Libby received her BS in Biochemistry and Molecular Biology from the University of Massachusetts Amherst in 2014. Before joining the Emerling Lab in 2019 she was a lab manager at the University of California San Diego. During her free time Libby enjoys doing puzzles, hiking, and playing roller derby.

 

RYAN LOUGHRAN

Graduate Student

Ryan recieved his BS in Biology from the University of Pittsburgh. Before joining the Emerling lab in 2016, Ryan was a research technician in the Cantley Lab at Weill Cornell Medicine. As a graduate student in the Emerling lab, he is currently focusing on uncovering the mechanism by which the PI5P4K enzymes act as compensatory metabolic sensors in p53 mutant cancers. In his spare time, he enjoys golf, tennis, and attempting to write the next Hugo award winning sci-fi novel.

 

ARCHNA RAVI

Postdoctoral Fellow

Archna received her MS in Molecular Biology from the University of Madras (2008) and her Ph.D. from National University of Singapore (2013) where she worked on RhoGTPase signaling in cell migration. Before joining the Emerling Lab in 2017, she was a postdoc at UC Irvine. Archna's research interests include understanding how the PI5P4K enzymes regulate intricate aspects of cell biology and their role(s) in metabolism and cancer. Outside the lab, Archna enjoys books, beaches, and traveling. 

LAVINIA PALAMIUC

Postdoctoral Fellow

Lavinia received her master's degree in Biotechnology from the University of Iasi, Romania (2010) and her PhD in Neuroscience from the University of Strasbourg, France (2014). Her PhD research focused on pre-symptomatic metabolic alterations in muscle tissue in a mouse model for amyotrophic lateral sclerosis. Before joining the Emerling Lab, she was a post-doc at The Scripps Research Institute where she studied fat metabolism and neuroendocrine signaling in C.elegans in Dr. Srinivasan's lab. Currently she is studying the role of PI5P4K enzymes in metabolic homeostasis and pathology. In her free time, Lavinia enjoys reading, photography, learning new languages, and hiking.

GURPREET ARORA

Postdoctoral Fellow

Gurpreet received her PhD in Cell and Molecular Biology from The University of Rochester. Before joining the Emerling lab, she was a postdoc at UT Southwestern Medical Center where she worked on identifying and characterizing factors that drive cancer cachexia, with the focus being on adipose wasting. Currently her research aims at understanding the biology of PI5P4K enzymes in cancer metabolism. Gurpreet enjoys photography, traveling and playing sports during her spare time.

VIVIAN TIEU

Undergraduate Student

Vivian is currently a student at UC San Diego and on track to receive her BS in Human Biology in June 2020.  As an aspiring pre-med, she joined the Emerling Lab with hopes in gaining more insight on the variety of facets of medicine. During her free time, Vivian enjoys reading, biking, and exploring new “foodie” places. 

SARAH FORTE

Administrative Assistant

Sarah received her BA in Business Marketing from San Diego State University and a  Bachelor of Science in Business Administration from the University of Phoenix. Prior to joining SBP she was a Marketing Manager at the Institute for Health Maintenance.  Sarah was born and raised in Southern California. She spends most of her free time with her 2-year-old daughter and husband enjoying all that San Diego as to offer. She is a certificated Pilates instructor and continues to practice Pilates today.

LAB ALUMNI

Ann Pham (Research Associate, 2017-2018) - Currently: Research Associate, Organovo Holdings, Inc.

Oscar Donosa (Undergraduate student, 2017) - Currently: UCSD undergraduate 

LAB NEWS

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Emerling Lab Axes Cancer!

August 24, 2019

Annual summer outing to Bad Axe Throwing! 

Fast Pitch Winner!

March 05, 2019

Brooke wins the the Fast Pitch competition at the Susan G. Komen Metastatic Breast Cancer Conference! Go team Emerling Lab!

University of Bern Visit!

August 16, 2018

Amazing visit to University of Bern! Many thanks to the Rubin Lab! 

Archna wins FASEB travel award!

August 01, 2018

Archna gave an amazing talk, presented a poster and received the travel award at the 2019 FASEB Phospholipids: Dynamic Lipid Signaling in Health and Disease Conference in Steamboat Colorado. 

Just a normal day in the Emerling Lab!

June 20, 2017

Emerling Lab was entertained and thrilled to have musician and science enthusiast Tom DeLonge tour the lab! 

The Emerling Lab is Growing 🌱🔬🐁

March 15, 2017

The Emerling Lab is excited to welcome new scientists to the team. Stay tuned for exciting research news from the Emerling Lab at SBP Medical Discovery Institute!

Komen San Diego Race for the Cure – Great job Team SBP!

November 06, 2016

The Emerling Lab joined with other labs at SBP and friends to help raise over $1 million for breast cancer research.

Breast Cancer Research Foundation 2016 Symposium and Awards Luncheon Raises More Than $2 Million

October 28, 2016

On Thursday, October 27 at the Waldorf Astoria in New York City, the Breast Cancer Research Foundation (BCRF) held its annual Symposium and Awards Luncheon to celebrate BCRF's announcement of $57 million in grants awarded to more than 250 breast cancer investigators around the world. The event raised more than $2 million with 900 guests in attendance to support breast cancer research.

October is Breast Cancer Awareness Month

October 03, 2016

Laura Farmer Sherman - president and CEO of Susan G. Komen San Diego - is celebrating the local scientists working to find new drugs to treat breast cancer and find a cure. Koman San Diego currently has more than one million dollars in active research grants at work in San Diego. Dr. Brooke Emerling, Preby's Medical Discovery Institute, studies certain genes and mutations and believes scientists are on the verge of finding a cure.

Emerling Lab Inaugural Happy Hour

August 26, 2016

The Emerling Lab welcomed friends and lab team to an inaugural happy hour in Del Mar. The event marks the beginning of great research and collaboration at the SBP Medical Discovery Institute.

Sanford Burnham Prebys Recruits Rising Star In Cancer Research

August 16, 2016

Brooke Emerling, Ph.D., has joined the Sanford Burnham Prebys Medical Discovery Institute (SBP) as an assistant professor in the Cancer Metabolism and Signaling Networks Program. She brings a pioneering research program with strong potential to yield new cancer therapies.

Emerling Lab Opens

August 01, 2016

The Emerling Lab moves into new facitilites at the SBP Medical Discovery Institute.

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OPEN POSITIONS

Post Doc
Lab Manager
Research Assistant
Undergraduate Student
 
LINKS
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Tel: 848-646-3100

10901 North Torrey Pines Road

La Jolla, CA 92037

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