PMID- 10427092
OWN - NLM
STAT- MEDLINE
DCOM- 19990826
LR  - 20190508
IS  - 0021-9525 (Print)
IS  - 0021-9525 (Linking)
VI  - 146
IP  - 2
DP  - 1999 Jul 26
TI  - Shc and FAK differentially regulate cell motility and directionality modulated by
      PTEN.
PG  - 389-403
AB  - Cell migration is modulated by regulatory molecules such as growth factors,
      oncogenes, and the tumor suppressor PTEN. We previously described inhibition of
      cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK)
      and p130 Crk-associated substrate (p130(Cas)). We now report a novel pathway
      regulating random cell motility involving Shc and mitogen-activated protein (MAP)
      kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating
      directional migration. Overexpression of Shc or constitutively activated MEK1 in 
      PTEN- reconstituted U87-MG cells stimulated integrin- mediated MAP kinase
      activation and cell migration. Conversely, overexpression of dominant negative
      Shc inhibited cell migration; Akt appeared uninvolved. PTEN directly
      dephosphorylated Shc. The migration induced by FAK or p130(Cas) was directionally
      persistent and involved extensive organization of actin microfilaments and focal 
      adhesions. In contrast, Shc or MEK1 induced a random type of motility associated 
      with less actin cytoskeletal and focal adhesion organization. These results
      identify two distinct, additive pathways regulating cell migration that are
      downregulated by tumor suppressor PTEN: one involves Shc, a MAP kinase pathway,
      and random migration, whereas the other involves FAK, p130(Cas), more extensive
      actin cytoskeletal organization, focal contacts, and directionally persistent
      cell motility. Integration of these pathways provides an intracellular mechanism 
      for regulating the speed and the directionality of cell migration.
FAU - Gu, J
AU  - Gu J
AD  - Craniofacial Developmental Biology and Regeneration Branch, National Institute of
      Dental and Craniofacial Research, National Institutes of Health, Bethesda,
      Maryland 20892-4370, USA.
FAU - Tamura, M
AU  - Tamura M
FAU - Pankov, R
AU  - Pankov R
FAU - Danen, E H
AU  - Danen EH
FAU - Takino, T
AU  - Takino T
FAU - Matsumoto, K
AU  - Matsumoto K
FAU - Yamada, K M
AU  - Yamada KM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Actins)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (BCAR1 protein, human)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Crk-Associated Substrate Protein)
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (Integrins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Proteins)
RN  - 0 (Retinoblastoma-Like Protein p130)
RN  - 0 (SHC1 protein, human)
RN  - 0 (Shc Signaling Adaptor Proteins)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.1.- (FAK-related nonkinase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Actins/metabolism
MH  - *Adaptor Proteins, Signal Transducing
MH  - *Adaptor Proteins, Vesicular Transport
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Cell Adhesion
MH  - Cell Adhesion Molecules/genetics/*metabolism
MH  - *Cell Movement
MH  - Crk-Associated Substrate Protein
MH  - Culture Media, Serum-Free
MH  - Cytoskeleton/metabolism
MH  - Enzyme Activation
MH  - Focal Adhesion Kinase 1
MH  - Focal Adhesion Protein-Tyrosine Kinases
MH  - Genes, Dominant/genetics/physiology
MH  - Humans
MH  - Integrins/antagonists & inhibitors/metabolism
MH  - MAP Kinase Kinase 1
MH  - *Mitogen-Activated Protein Kinase Kinases
MH  - PTEN Phosphohydrolase
MH  - Phosphoproteins/genetics/metabolism
MH  - Phosphoric Monoester Hydrolases/antagonists & inhibitors/genetics/*metabolism
MH  - Phosphorylation
MH  - Protein Isoforms/genetics/metabolism
MH  - Protein-Serine-Threonine Kinases/genetics/metabolism
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Retinoblastoma-Like Protein p130
MH  - Shc Signaling Adaptor Proteins
MH  - Signal Transduction
MH  - Src Homology 2 Domain-Containing, Transforming Protein 1
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - *Tumor Suppressor Proteins
PMC - PMC2156182
EDAT- 1999/07/31 00:00
MHDA- 1999/07/31 00:01
CRDT- 1999/07/31 00:00
PHST- 1999/07/31 00:00 [pubmed]
PHST- 1999/07/31 00:01 [medline]
PHST- 1999/07/31 00:00 [entrez]
AID - 10.1083/jcb.146.2.389 [doi]
PST - ppublish
SO  - J Cell Biol. 1999 Jul 26;146(2):389-403. doi: 10.1083/jcb.146.2.389.