MICAL-1 Is a Negative Regulator of MST-NDR Kinase Signaling and Apoptosis

Abstract

Article abstract-Objective: To present the clinical, neuroimaging, and electrophysiologic characteristics of a variant AD phenotype. Background: The authors have identified a large Finnish kindred with presenile dementia and spastic paraparesis due to deletion of exon 9 of presenilin 1. Neuropathologic analysis showed unusual cortical "cotton wool" plaques, immunoreactive for the beta-amyloid peptide but lacking congophilic cores. Patients and Methods: Twenty-two affected individuals (16 men and 6 women) were identified in four successive generations. All surviving five patients were examined and subjected to molecular genetic analysis. In addition, the neurologic records of nine deceased patients were evaluated. Electrophysiologic investigations were available in eight cases. CT or MRI of the head had been performed on 11 patients and PET was performed on three patients. Result: The mean age at onset (ϮSD) was 50.9 Ϯ 5.2 years (range 40 to 61 years). Memory impairment was present in all patients. Memory impairment appeared simultaneously with or was preceded by walking difficulty due to spasticity of the lower extremities (10/14). Impaired fine coordination of hands (9/14) and dysarthria (6/14) in some patients suggested cerebellar involvement. EEG showed intermittent generalized delta-theta activity. Head MRI showed temporal and hippocampal atrophy; PET showed bilateral temporo-parietal hypometabolism. Conclusion: Spastic paraparesis or brisk stretch reflexes of lower extremities or clumsiness of hands combined with dementia suggests this variant of AD.

MICAL1 facilitates breast cancer cell proliferation via ROS‐sensitive ERK/cyclin D pathway

“…Oxidative stress originates from an imbalance between the generation and scavenging of ROS, activates aberrant signalling cascades and leads to tumorigenesis. A recent study reported that increased ROS production was triggered by overexpression of constitutively active MICAL1 mutants 16. On the contrary, ROS levels were significantly attenuated upon transfection of the enzymatically impaired FAD domain mutant 4.…”

“…Previous studies have reported the anti‐apoptosis effect of MICAL1 in human melanoma cells. The mechanism was demonstrated to be associated with MICAL1's negative control of mammalian Ste‐20‐like kinase 1 (MST1)‐nuclear‐Dbf2‐related kinase (NDR) apoptotic signalling by competing with MST1 for NDR binding 5, 16. Despite its characteristic on anti‐apoptosis, whether MICAL1 could influence cancer cell proliferation and the underlying molecular mechanism remains unclear.…”

RalA GTPase and MAP4K4 Function through NDR1 Activation in Stress Response and Apoptotic Signaling

“…NDR1 belongs to the NDR/LATS subgroup of the AGC serine/threonine kinase family [33,34] and is activated by Fas, TNF-α, osmotic and oxidative stresses [35][36][37]. Therefore, our Y2H results suggested that NDR1 might function together with RalA and MAP4K4 upstream of p38 activation in the osmotic stress response.…”

“…More specifically, our study expands our understanding of how RalA signaling pathways mediate SAPK activation and determines the role of RalA in apoptosis induced responses to different types of environmental stresses. We identified MAP4K4 as a new upstream kinase of NDR1 (also known as STK38), an AGC serine/threonine protein kinase [33,34] that can be activated by Fas, TNF-α, osmotic and oxidative stresses [35][36][37]. Moreover, we demonstrate that RalA regulates NDR1 activation, via Exocyst and MAP4K4 signaling, to trigger apoptosis in response of extracellular stresses.…”

“…Since RalA-Exocyst-MAP4K4 signaling regulates NDR1 activation (Figures 3-5) and NDR1 activation is necessary for efficient apoptosis signaling [35][36][37], the role of RalA in apoptosis caused by hyperosmolarity was explored in our settings (Figure 6). High osmolarity, such as 1 M sorbitol [57], but not 0.3 M sorbitol (data not shown), promoted after 2 hours the cleavage of caspase 3 ( Figure 6A), a well established marker for on-going apoptosis.…”