Altered MAP kinase phosphorylation and impaired motor coordination in PTPRR deficient mice

Abstract

The neuronal protein tyrosine phosphatases encoded by mouse gene Ptprr (PTPBR7, PTP-SL, PTPPBSc-42 and PTPPBSc-37) have been implicated in mitogen-activated protein (MAP) kinase deactivation on the basis of transfection experiments. To determine their physiological role in vivo, we generated mice that lack all PTPRR isoforms. The cerebellum is the major centre of fine motor coordination in the central nervous system, and in addition serves in cognitive processing and sensory discrimination. Abbreviations used: DUSP, dual-specificity phosphatase; ERK, extracellular signal-regulated kinase; KIM, kinase interaction motif; MAPK, mitogen-activated protein kinase; PTP, protein tyrosine phosphatase.

Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the ‘PTP-ome'

“…S10D). This is consistent with the role of PTPRR as an inhibitor of MAPK signaling (Chirivi et al 2007), and with our observation that enhanced cell motility induced by suppression of PTPRR was dependent on ERBB2 activation (Fig. 2).…”

Nasal speech and hypothyroidism are common hallmarks of 12q15 microdeletions

“…These mice displayed impaired motor coordination and defects in their balance skills, reminiscent of a mild ataxia because of altered MAPK signaling. 18 The protein encoded by TSPAN8 is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Tetraspanin 8 affects protein trafficking and is known to influence a wide variety of physiological processes.…”

PTPRR (protein tyrosine phosphatase, receptor type, R)

“…Furthermore, pharmacological inhibition (Paul et al, 2003;Valjent et al, 2005) and mouse knock-out studies also proved PTPN5 to be a physiological regulator of MAP kinase cascades (Venkitaramani et al, 2009). Indeed, also Ptprr knock-out mice displayed MAP kinase hyperphosphorylation in relevant tissues (Chirivi et al, 2007). PTPRR's closest homolog, the PTPN5-encoded protein STEP, is additionally capable of dephosphorylating the cytosolic tyrosine kinase Fyn, Pyk2, and subunits of AMPA and NMDA receptors in neuronal cells, implicating KIM-containing PTPs in neuronal functions like synaptic transmission (Baum et al, 2010;Xu et al, 2012a).…”

“…There is even evidence that PTPN5 is linked to the pathophysiology of diverse neuropsychiatric disorders in man, including Schizophrenia and Alzheimer's disease (Goebel-Goody et al, 2012;Xu et al, 2012b). Although direct evidence for an impact of PTPRR on Src-family kinase or AMPA and NMDA receptor subunit phosphorylation levels has not yet been obtained, it remains an interesting possibility in view of the phenotypic consequences of PTPRR deficiency in mice (Chirivi et al, 2007) and the proposed links with some human (neuro)pathological conditions (below).…”

“…Note Ptprr knockout mice display mild, ataxia-like, locomotive impairment (Chirivi et al, 2007) but the gene's location in human does not match with the various ataxia loci that have been mapped thus far and that still await identification of the underlying gene defects (Espinós et al, 2009). …”