Trk receptors use redundant signal transduction pathways involving SHC and PLC-γ1 to mediate NGF responses

Stephens, Robert M.; Loeb, David M.; Copeland, Terry D.; Pawson, Tony; Greene, Lloyd A.; Kaplan, David R.

doi:10.1016/0896-6273(94)90223-2

Cited by 521 publications

(526 citation statements)

References 74 publications

Supporting

Mentioning

492

Contrasting

Order By: Relevance

“…One of these, phosphotyrosine Y490, binds SHC proteins of 48 kD, 53 kD and, to a lesser extent, 68 kD. SHC proteins are thought to associate with Grb2 or Ras-GAP, both of which modulate p21 ras activity (Stephens et al, 1994). The other autophosphorylation site, tyrosine Y785, mediates association with and tyrosine phosphorylation of PLC-g (Obermeier et al, 1993a).…”

Section: Resultsmentioning

confidence: 99%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

View full text Add to dashboard Cite

Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER TM ®broblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.-and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-g binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinase inhibitors LY294002 and Wortmannin competely block survival signalling following U.V. treatment, neither drug a ects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate di erent survival signalling pathways, which can interfere with speci®c apoptotic pathways.

show abstract

Section: Resultsmentioning

confidence: 99%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

View full text Add to dashboard Cite

show abstract

“…Using the oncogenic TrkA protein, single phenylalanine substitutions at tyrosines 503 or 504 (corresponding to TrkB Y674 and Y675) resulted in a dramatic decrease in both in vitro kinase activity and transformation potential. Stephens et al (1994) showed that a proto-oncogene derived TrkA protein containing phenylalanine substitutions at both tyrosines 674 and 675 resulted in autophosphorylation de®cient receptors. However, Segal et al (1996) showed that phosphorylation of TrkA Y490 occurs in receptors containing a YY674/675FF double substitution, indicating the presence of catalytic activity in these receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Based on its neighboring N-terminal amino acid sequence (NPQY), Y484 is predicted to be the binding site for the PTB domain of the SHC adapter protein. Indeed, the corresponding phosphorylated tyrosine (pY490) in TrkA is responsible for the NGF-inducible association of TrkA with SHC (Obermeier et al, 1993b;Stephens et al, 1994;Dikic et al, 1995). Tyrosine 785 is in the extreme C-terminal region of TrkB.…”

Section: Introductionmentioning

confidence: 99%

Activation loop tyrosines contribute varying roles to TrkB autophosphorylation and signal transduction

McCarty

Feinstein

1998

Oncogene

View full text Add to dashboard Cite

The TrkB receptor tyrosine kinase (RTK) is a high a nity receptor for the neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5). Following exposure to BDNF or NT-4/5, TrkB is autophosphorylated on ®ve cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Based on crystallographic analyses for others RTKs, TrkB tyrosines Y670, Y674, and Y675 are expected to lie within a putative kinase activation loop. Phosphorylation of these activation loop tyrosines is postulated to be a conserved event required for complete RTK activation. Here, we have assessed the importance these activation loop tyrosines play in regulating TrkB autophosphorylation, cytoplasmic signal transduction, and cell proliferation. We show that while tyrosine 670 is dispensable for BDNF-inducible TrkB autophosphorylation and the activation of certain signal transduction events, it is required for complete TrkBmediated cellular proliferation. Combinatorial mutagenesis of tyrosines 674 and 675 only moderately a ects TrkB autophosphorylation, but signi®cantly impairs the BDNF-inducible stimulation of cytoplasmic signaling events and cellular proliferation. The combined mutation of all three activation loop tyrosines results in an inactive receptor, which is unable to autophosphorylate, stimulate signaling events, or induce mitogenesis. The data highlight the varying degrees of importance of the three activation loop tyrosines in TrkB mediated biological responses.

show abstract

“…While not all of these intracellular targets directly interact with TrkA, several studies indicate that Tyr 499 is essential to the phosphorylation and receptor binding of the PTB domains of Shc (Obermeier et al, 1993;Stephens et al, 1994) and FRS-2 (Meakin et al, 1999). As discussed above, Tyr 794 is essential for the phosphorylation and binding of PLCg-1 and the soluble tyrosine kinase, CHK (Yamashita et al, 1999).…”

Section: Signal Transductionmentioning

confidence: 98%

“…The catalytic core tyrosines (Tyr 679 , Tyr 683 and Tyr 684 ) are essential to receptor phosphorylation and activation while Tyr 499 and Tyr 794 are required for the tyrosine phosphorylation of Shc/ FRS-2 and PLCg-1/CHK, respectively, and serve as the docking sites for their high-a nity binding to TrkA (Obermeier et al, 1994;Stephens et al, 1994;Meakin et al, 1999;Yamashita et al, 1999).…”

mentioning

confidence: 99%