PMID- 23460911
OWN - NLM
STAT- MEDLINE
DCOM- 20130903
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 2
DP  - 2013
TI  - The tandem PH domain-containing protein 2 (TAPP2) regulates chemokine-induced 
      cytoskeletal reorganization and malignant B cell migration.
PG  - e57809
LID - 10.1371/journal.pone.0057809 [doi]
LID - e57809
AB  - The intracellular signaling processes controlling malignant B cell migration and 
      tissue localization remain largely undefined. Tandem PH domain-containing 
      proteins TAPP1 and TAPP2 are adaptor proteins that specifically bind to 
      phosphatidylinositol-3,4-bisphosphate, or PI(3,4)P2, a product of 
      phosphoinositide 3-kinases (PI3K). While PI3K enzymes have a number of functions 
      in cell biology, including cell migration, the functions of PI(3,4)P2 and its 
      binding proteins are not well understood. Previously we found that TAPP2 is 
      highly expressed in primary leukemic B cells that have strong migratory capacity. 
      Here we find that SDF-1-dependent migration of human malignant B cells requires 
      both PI3K signaling and TAPP2. Migration in a transwell assay is significantly 
      impaired by pan-PI3K and isoform-selective PI3K inhibitors, or by TAPP2 shRNA 
      knockdown (KD). Strikingly, TAPP2 KD in combination with PI3K inhibitor treatment 
      nearly abolished the migration response, suggesting that TAPP2 may contribute 
      some functions independent of the PI3K pathway. In microfluidic chamber cell 
      tracking assays, TAPP2 KD cells show reduction in percentage of migrating cells, 
      migration velocity and directionality. TAPP2 KD led to alterations in 
      chemokine-induced rearrangement of the actin cytoskeleton and failure to form 
      polarized morphology. TAPP2 co-localized with the stable F-actin-binding protein 
      utrophin, with both molecules reciprocally localizing against F-actin accumulated 
      at the leading edge upon SDF-1 stimulation. In TAPP2 KD cells, Rac was 
      over-activated and localized to multiple membrane protrusions, suggesting that 
      TAPP2 may act in concert with utrophin and stable F-actin to spatially restrict 
      Rac activation and reduce formation of multiple membrane protrusions. TAPP2 
      function in cell migration is also apparent in the more complex context of B cell 
      migration into stromal cell layers - a process that is only partially dependent 
      on PI3K and SDF-1. In summary, this study identified TAPP2 as a novel regulator 
      of malignant B cell migration and a potential therapeutic intervention target.
FAU - Li, Hongzhao
AU  - Li H
AD  - Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
FAU - Hou, Sen
AU  - Hou S
FAU - Wu, Xun
AU  - Wu X
FAU - Nandagopal, Saravanan
AU  - Nandagopal S
FAU - Lin, Francis
AU  - Lin F
FAU - Kung, Sam
AU  - Kung S
FAU - Marshall, Aaron James
AU  - Marshall AJ
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130227
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Actins)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (PLEKHA2 protein, human)
RN  - 0 (Utrophin)
RN  - EC 3.6.5.2 (rac GTP-Binding Proteins)
SB  - IM
MH  - Actin Cytoskeleton/drug effects/*metabolism
MH  - Actins/metabolism
MH  - B-Lymphocytes/drug effects/metabolism/*pathology
MH  - Cell Movement/*drug effects
MH  - Chemokine CXCL12/*pharmacology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Leukemia/*pathology
MH  - Lymphoma/*pathology
MH  - Membrane Proteins/*metabolism
MH  - Mesenchymal Stem Cells/drug effects/metabolism/pathology
MH  - Protein Transport/drug effects
MH  - Utrophin/metabolism
MH  - rac GTP-Binding Proteins/metabolism
PMC - PMC3583899
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/03/06 06:00
MHDA- 2013/09/04 06:00
PMCR- 2013/02/27
CRDT- 2013/03/06 06:00
PHST- 2012/09/09 00:00 [received]
PHST- 2013/01/26 00:00 [accepted]
PHST- 2013/03/06 06:00 [entrez]
PHST- 2013/03/06 06:00 [pubmed]
PHST- 2013/09/04 06:00 [medline]
PHST- 2013/02/27 00:00 [pmc-release]
AID - PONE-D-12-27478 [pii]
AID - 10.1371/journal.pone.0057809 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(2):e57809. doi: 10.1371/journal.pone.0057809. Epub 2013 Feb 27.