PTEN (Phosphatase and Tensin Homolog) a.k.a. MMAC1, TEP1 Raymond Stadiem.

Slides:



Advertisements
Similar presentations
Signal Transduction Mechanisms Underlying Underlying Growth Control and Oncogenesis Ronit Sagi-Eisenberg Dept. of Cell and Developmental Biology Sackler.
Advertisements

NF  B 9/2002 SFRBM Education Program Emily Ho 1 NF  B – What is it and What’s the deal with radicals? Emily Ho, Ph.D Linus Pauling Institute Scientist.
The Cell Cycle and Cancer. Cell signaling: chemical communication between cells. Click on above to go to animation second chemical response inside the.
PROLIFERAZIONE CELLULARE E RESISTENZA AI FARMACI.
Chap. 21 Stem Cells, Cell Asymmetry, and Cell Death Topics Cell Death and Its Regulation Goals Learn the basic mechanism of apoptosis and its regulation.
Gene regulation in cancer 11/14/07. Overview The hallmark of cancer is uncontrolled cell proliferation. Oncogenes code for proteins that help to regulate.
ApoptosisNecrosis Apoptosis is a form of programmed cell death Apoptosis is responsible for the formation of digits in the developing mouse paw. Apoptotic.
C-Kit and Gastrointestinal Stromal Tumors By Jessica Danielle Stewart
ZAFIA ANKLESARIA Role of BMPR1A in Juvenile Polyposis Syndrome Biology 169.
Phosphatase and Tensin Homolog Deleted on Chromosome 10
P53 gene mutations in human tumors Greenblatt et al. (1995) Cancer Res. 54: %
Protein Mutations in Disease Lecture 11, Medical Biochemistry.
BRCA Genes Dallas Henson.
RET Proto-Oncogene of Multiple Endocrine Neoplasia type 2(MEN2)
RET Proto- Oncogene in The Development of Thyroid Cancer: Multiple Endocrine Neoplasia Type 2 Courtney Brooks.
Cytoplasmic Signaling Circuitry Programs Many of the Traits of Cancer
Malignant Melanoma and CDKN2A
NOTES: CH 18 part 2 - The Molecular Biology of Cancer
Tumorigenesis to Cancer Development Pin Ling ( 凌 斌 ), Ph.D. ext 5632; References: 1.Chapter 23 Cancer in “Molecular Cell Biology”
Computational biology of cancer cell pathways Modelling of cancer cell function and response to therapy.
Cell Cycle Clock, Mitosis, and Cancer Biology HAP Lemon Bay High School Susan Chabot
BRCA1: Tumor Suppression and Breast Cancer A breast cancer cell dividing.
Cancer When cell division goes wrong……. Growing out of control, cancer cells produce malignant tumors Cancer is a general term for many diseases in.
Genetics of Cancer Genetic Mutations that Lead to Uncontrolled Cell Growth.
FGFR3 and Bladder Cancer Amy Fair March 29, 2005 Biol 169.
BMP Receptor 1A Juvenile Polyposis Dayna Neo 3/21/13 Biol
Ishita Das
CELL CYCLE.
Benign Versus Malignant Tumors
Src Kinase Biosensor. Outline 1.Src Kinase Introduction 2.Impacts of Src 3.Src reporter components  FPs (tECFP/EYFP)  SH2  Flexible linker  Substrate.
CHAPTER 19 THE ORGANIZATION AND CONTROL OF EUKARYOTIC GENOMES Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings Section D: The.
Genetics of Cancer Genetic Mutations that Lead to Uncontrolled Cell Growth.
Src Kinase Activity upon substrate phosphorylation.
MECHANISM OF ACTION STUDIES IN A549 CELLS SHOW THAT MARCKS-INHIBITORY PEPTIDES (IN THIS CASE MANS PEPTIDE) BLOCKS PHOSPHORYLATION OF MARCKS IN RESPONSE.
TSC1 and Facial Angiofibromas
BMP receptor1A Presented by Jena Buchan
PTEN and its Role in Cowden Syndrome and Sporadic Cancers John Cuningham Biology 445.
TSC1/Hamartin and Facial Angiofibromas Biology 169 Ann Hau.
PTEN (Cowden Syndrome) /.../ sld083.htm.
Merlin, tumor suppressor 박건수 Cancer Genetics.
Cowden’s Disease and PTEN. Cowden’s Disease (CD)  A rare autosomal dominant disease similar to Lehrmitte-Duclos Disease (LDD) and Bannayan-Zonana Syndrome.
Integrin-EGFR Cross-Activation Elizabeth Brooks Department of Chemical Engineering University of Massachusetts, Amherst Peyton Lab Group Meeting December.
The Problem of Cancer. What are cancer cells ? Cancerous growth involves unrestrained proliferation (malignancy) and spread (metastasis). Caused by: mutations.
Colon cancer: the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development
Date of download: 7/5/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. Insulin signaling pathways. The insulin signaling pathways provide.
Mouse Double Minute 2 (MDM2)
Integrin signalling Vytášek 2010.
Peyton Rous discovered a virus that causes cancer in chickens
Regulation of Cell Division
Cancer Biology Jasmina Makarevic
Cancer Genetics Genetics.
Bone Morphogenetic Protein Receptor 1A (BMPR1A) and Juvenile Polyposis Syndrome Cara Davidson March 18, 2004.
and multiple endocrine neoplasia type 2 (MEN2)
Tuberous Sclerosis TSC2/ Tuberin Alison Chappell.
Chap. 16 Problem 1 Cytokine receptors and RTKs both form functional dimers on binding of ligand. Ligand binding activates cytosolic kinase domains which.
TSC1 in Facial Angiofibromas
TSC2 GENE ENCODES FOR TUBERIN
PTEN (a.k.a. MMAC1 and TEP1) and Cowden’s Disease
Graduate School of Medical Science & Egineering
The Role of Patch in Basal Cell Carcinoma
Figure 1 A schematic representation of the HER2 signalling pathway
Integrin signalling Vytášek 2009.
PTEN Tumor Suppressor Extraordinaire
PTEN Tumor Suppressor and Cancer
Development of PI3K/AKT/mTOR Pathway Inhibitors and Their Application in Personalized Therapy for Non–Small-Cell Lung Cancer  Vassiliki Papadimitrakopoulou,
BMP Receptor 1a and Juvenile Polyposis Syndrome
PKB Binding Proteins Cell
Multifunctional Tumor Suppressor
Successful targeting of ErbB2 receptors—is PTEN the key?
Presentation transcript:

PTEN (Phosphatase and Tensin Homolog) a.k.a. MMAC1, TEP1 Raymond Stadiem

PTEN - Overview What is PTEN?  Biochemistry/Cell Biology of PTEN protein Biological function of the Pten gene Why did Peifer and Duronio want us to know about PTEN?

Many proto-oncogenes are kinases (ex: Ras, Src) THEREFORE, it would make sense if there existed tumor suppressors, which regulate this activity by being … PHOSPHATASES

What is PTEN? PTEN was discovered in 1997 as the first tumor suppressor phosphatase Phosphatase and Tensin Homolog

PTEN is a phosphatase with two types of substrates (1)Lipid substrate (primary substrate)-involved in cell signaling key target: phosphatidylinositol 3,4,5- trisphosphate(P 3 ) Yamada et al., 2001

PTEN and PI-3 Kinase act as antagonists in lipid signaling Comer et al., 2002

PTEN activation of Akt/PKB Initiated by binding of growth factors (ex:TGF, Insulin) to receptors Upon ligand binding to growth factor receptor, PI-3 Kinase is activated PI-3 Kinase phosphorylates and activates PtdIns(3,4,5)P 3 PtdIns(3,4,5)P 3 signals Akt/PKB PTEN dephosphorylates and inhibits PtdIns(3,4,5)P 3 (level of regulation)

PTEN is a lipid 3-phosphatase, which signals down the PI3 kinase/AKT proapoptotic pathway. Backman et al.

Outcomes of the Akt/PKB pathway Role in proliferation complicated PTEN does not merely block proliferation because studies showed that normal bacteria cells expressing PTEN can still undergo rapid proliferation (Liliental et al., 2000) Role in apoptosis more clear Re-expression of PTEN in several carcinoma cell lines induces apoptosis (Li et al, 1998) Especially important is Anoikis, a form of apoptosis that occurs when cells lose contact with the e.c.m. - mediates the cell’s “anchorage dependence” (Davies et al., 1998)

PTEN is a phosphatase with two types of substrates (part 2) (2) PTEN may be also a weak protein phosphatase for protein phosphate substrates - can remove phosphate groups from Ser, Thr, and Tyr residues (mechanisms still unclear) 2 cytoplasmic phosphoprotein substrates: Focal Adhesion Kinase (FAK) and adapter protein Shc Pathway activated by Integrins and other transmembrane receptors and leads to control of mobility and adhesion of cells

Reported Sites of Action of PTEN Yamada et al. 2001

Localization of signaling proteins during migration Comer et al., 2002 PI3K and PTEN show reciprocal localizations during chemotaxis

PTEN has an N-Terminal Phosphatase Domain and C-Terminal C2 Domain Lee et al., 1999

What about the Pten gene?

Pten is a tumor suppressor gene that is essential for embryonic development Pten gene located on Chrom 10 (10q23) Several different Pten null mice lines were generated-produced varying results depending upon which genetic background of mouse was used (e.g.129SvEv vs. C57Bl6) But in all cases mice do NOT survive to birth  PTEN required for embryogenesis

Pten -/- cells show increased ability to develop teratomas Di Cristofano et al., 1998

Pten is a key player in 3 human autosomal dominant diseases Cowden Disease (CD),Lhermitte-Duclos Disease (LDD),Bannayan-Zonana Syndrom (BZS) In all 3 disorders, germline mutations in PTEN have been observed Still unclear why mutation in one gene leads to 3 related yet distinct disorders Develop hamartomas of the skin, thyroid, breast, GI tract, CNS, and endometrium Breast cancers develop in 25-50% of affected women and thyroid cancer in 3-10% of all affected individuals Ali et al., 1999

Harmatomas, a common symptom 3 PTEN related diseases characterized by multiple harmatomas A focal malformation that grows by cellular proliferation more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease results from faulty development in an organ; composed of an abnormal mixture of tissue elements, or an abnormal proportion of a single element, normally present in that site, which develop and grow at virtually the same rate as normal components, and are not likely to result in compression of adjacent tissue (in contrast to a neoplasm). MD_info/md_Cowden_sy.htm

PTEN: What might go wrong? With PTENWithout PTEN Echelon Biosciences

How is Pten involved in cancer? Most frequently mutated gene identified yet in endometrial cancers (33-55% of tumors examined)-Mostly FS, MS, and NS mutations Of 647 Malignant Glial Tumors examined, 24% showed mutations in PTEN- mostly MS and FS mutations Ovarian tumors (of endometriod origin) showed mutations in 26% of tumors - mostly MS, FS, and NS mutations Prostate Carcinoma-mutations in 18% of tumors-Homozygous Deletions, and FS mut. Ali et al., 1999

Summary PTEN is both a lipid and protein phosphatase Shown to be involved in pathways that involve apoptosis (or anoikis), mobility, and cell adhesion PTEN is necessary for embryogenesis and may also control tumor development in mice PTEN involved in 3 major genetic diseases with mutations in one gene that cause similar yet distinct phenotypes PTEN mutated in many cancers but more needs to be learned about the pathways involved to better understand how cancers arise and to determine how to design new therapeutic treatments

“PTEN appears to serve as a hub or switchport linking complex signaling pathways. Its disruption…can be likened to disrupting a hub on the internet…(what we have learned about) possible regulations still need clarification.” Yamada et al. 2001