Protein tyrosine phosphatase alpha (PTPα) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety

Skelton, Matthew R.; Ponniah, Sathivel; Wang, Dennis Z.-M.; Doetschman, Thomas; Vorhees, Charles V.; Pallen, Catherine J.

doi:10.1016/s0006-8993(03)02839-7

Cited by 50 publications

(35 citation statements)

References 37 publications

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“…These include PTP-a, PTP-E, SHP-1, SHP-2, and PTP1B. Among them, PTP-a has been shown to activate Src during mitosis (14) and in neuronal differentiation (15,16). PTP-E has been implicated in regulating Src in osteoclast precursor cells (17).…”

Section: Introductionmentioning

confidence: 99%

PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation

2007

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Src-specific activity has been reported to be elevated in a high percentage of colon cancer cell lines and tumors, but the underlying mechanisms are largely unknown. In this study, we report that, in the seven cancer cell lines tested, Src-specific activity was elevated (5.2-to 18.7-fold) relative to normal colon cells (FHC). This activation of Src correlated with reduced phosphorylation at Y530 of Src, whereas there was no significant change in the level of phosphorylation at Y419. The membrane tyrosine phosphatase activity for a Src familyspecific phosphopeptide substrate FCP (Fyn COOH-terminal peptide phosphorylated by Csk) was greatly increased in the cancer cells and was attributed to PTP1B in most of the cell lines. Membrane PTP1B protein levels were also greatly increased. Overexpression of PTP1B increased Src specific activity in colon cancer cells by reducing phosphorylation at Y530 of Src. It also increased anchorage-independent cell growth and this increase was blocked by the Src inhibitor PP2 and Src small interfering RNA (siRNA). Down-regulating PTP1B activity by PTP1B inhibitor CinnGEL 2Me or knocking down PTP1B using siRNA also reduced Src kinase activity and colony formation ability of colon cancer cells. PTP1B siRNA reduced tumor growth in nonobese diabetic/severe combined immunodeficient mice. This study suggests that (a) PTP1B can act as an important activator of Src in colon cancer cells via dephosphorylation at Y530 of Src and (b) elevated levels of PTP1B can increase tumorigenicity of colon cancer cells by activating Src.

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Section: Introductionmentioning

confidence: 99%

PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation

2007

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“…It has been shown that the inside-out radial migration is preserved in RPTP␣ -/-mice, but the disorganization of the hippocampal layers indicates that RPTP␣ -/-neurons migrated at lower rates during initial soma translocation or along the radial glia at later developmental stages. Long-term potentiation (LTP) and spatial learning were also impaired in RPTP␣-deficient mice (Petrone et al, 2003), and anxiety was reduced (Skelton et al, 2003). Interestingly, Fyn-knockout mice display similar phenotype (Grant et al, 1992;Kojima et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

RPTPα is required for rigidity-dependent inhibition of extension and differentiation of hippocampal neurons

Kostić

Sap

Sheetz

2007

Journal of Cell Science

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Receptor-like protein tyrosine phosphatase α (RPTPα)-knockout mice have severe hippocampal abnormalities similar to knockouts of the Src family kinase Fyn. These enzymes are linked to the matrix-rigidity response in fibroblasts, but their function in neurons is unknown. The matrix-rigidity response of fibroblasts appears to differ from that of neuronal growth cones but it is unknown whether the rigidity detection mechanism or response pathway is altered. Here, we report that RPTPα is required for rigidity-dependent reinforcement of fibronectin (FN)-cytoskeleton bonds and the rigidity response in hippocampal neuron growth cones, like in fibroblasts. In control neurons, rigid FN surfaces inhibit neurite extension and neuron differentiation relative to soft surfaces. In RPTPα–/– neurons, no inhibition of extension and differentiation is found on both rigid and soft surfaces. The RPTPα-dependent rigidity response in neurons is FN-specific, and requires clustering of αvβ6 integrin at the leading edge of the growth cones. Further, RPTPα is necessary for the rigidity-dependent concentration of Fyn and p130Cas phosphorylation at the leading edge of the growth cone, like it is in fibroblasts. Although neurons respond to rigid FN surfaces in the opposite way to fibroblasts, we suggest that the mechanism of detecting FN rigidity is similar and involves rigidity-dependent RPTPα recruitment of Fyn.

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“…Preclinical and clinical studies suggest that there exists a neurobiological link between emotional and cognitive processes (Bell and Wolfe, 2004;Clark and McManus, 2002;Ishigooka, 2003;Skelton et al, 2003). Accordingly, anxiety disorders may result from an overexpression of aversive memories (Crestani et al, 1999;Pare, 1996).…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

Degroot

Nomikos

2004

Neuropsychopharmacol

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Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac s ) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.

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Protein tyrosine phosphatase alpha (PTPα) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety

Cited by 50 publications

References 37 publications

PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation

PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation

RPTPα is required for rigidity-dependent inhibition of extension and differentiation of hippocampal neurons

Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

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