Platelet-activating factor acetylhydrolase IB subunit alpha (PAFAH1B1) (LIS1)

LIS1, also known as Platelet-activating factor acetylhydrolase IB subunit alpha (PAFAH1B1), is a critical regulatory protein primarily recognized for its essential role in brain development and neuronal migration [1, 5]. It functions as a non-catalytic subunit of the intracellular platelet-activating factor acetylhydrolase IB complex and acts as a key regulator of the cytoplasmic dynein motor protein [4, 9]. By binding to the dynein motor domain, LIS1 prevents the motor from entering an autoinhibited state, thereby facilitating the transport of various cellular cargoes along microtubules [22, 29]. Mutations or deletions in the PAFAH1B1 gene lead to severe neurodevelopmental disorders, most notably Type 1 lissencephaly and Miller-Dieker syndrome, which are characterized by a smooth brain appearance due to defective neuronal positioning [2, 3, 8]. Beyond its role in development, LIS1 is increasingly investigated as a therapeutic target in oncology, particularly in aggressive cancers like triple-negative breast cancer and glioblastoma, where it influences cell cycle progression and sensitivity to microtubule-targeting agents like paclitaxel [23, 33]. Experimental strategies to modulate LIS1 include the use of calpain inhibitors to stabilize the protein in cases of haploinsufficiency [20, 24]. However, the protein's dosage sensitivity and fundamental role in mitosis present significant safety challenges for drug development [3, 30]. Notably, the name LIS1 is also used for a clinical-stage anti-lymphocyte antibody developed by Xenothera, which is distinct from the LIS1 protein target [21, 26].

Other names

PAFAH1B1Lissencephaly-1 proteinLIS-1PAFAHLIS2MDCRMDSPlatelet-activating factor acetylhydrolase 1b regulatory subunit 1NudF

Stabilization of LIS1 protein by inhibiting calpain-mediated degradation; modulation of dynein-mediated transport and microtubule stability.