Par (for partition defective) proteins are evolutionary conserved proteins, which are involved in regulating axon specification and establishment of neuronal polarity. These proteins are first discovered in the C.elegans, which has 6 par genes named as par1-6.
s. no
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Par proteins
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In C.elegans
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Drosophila homolog
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Mammalian homolog
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Involvement in neuronal polarity?
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1
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Par1
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Serine/Threonine kinase
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Par 1
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MARK kinase
SAD kinase
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Yes
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2
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Par2
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Zinc finger and ATP binding motif (ubiquitination pathway)
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Not conserved
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Not conserved
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unknown
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3
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Par3
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Scaffold (PDZ domains)
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Bazooka
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mPar3 (also called as ASIP PHIP)
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Yes
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4
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Par4
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Serine/Threonine kinase
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Par4
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LKB1
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Yes
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5
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Par5
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14-3-3 protein
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Par5
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14-3-3 protein
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Unknown
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6
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Par6
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Scaffold
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Par6
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mPar6
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Yes
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Par3/Par6/aPKC complex in neuronal polarity
Par3/Par6/aPKC complex plays a crucial role in axon specification and polarity establishment in a cultured hippocampal neuron. These complexes (Par3/Par6) are selectively enriched at tip of the future axon, inorder to make the cell polarized. If the complex expression is inhibited, then the neurite differentiating to axon and dendrite does not take place. If the complex is over expressed, then multiple axon or dendrite is formed.
The par3 and par6 are scaffold proteins, where Par 3 interacts with Par6 and with Tiam1 (T-lymphoma invasion and metastasis 1) and GNEF (Guanine nucleotide exchange factor) for Rac. Par6 forms a stable complex with aPKC (protein kinase C) and contains a semi- cdc42/Rac interactive binding (CRIB) domain that specifically binds to the active GTP bound form of the small GTPases, Cdc42 and Rac1 (central regulators of actin cytoskeletal dynamics).
It also regulation of these par complexes is responsible for the control in morphogenesis of dendritic spines.
Cdc42 which is activated by the PIP3 will initiate the positive feedback loop by binding to the Par6 protein.
The par3/par6/aPKC complex will then activate Rac GEF which has STEF/ Tiam1 protein bind to it. This activated Rac complex will activate the Rac, a small GTPase protein and finally triggers the PI3 kinase. PI3 kinase is the important enzyme in neuronal polarity and axonal specification because it converts the PIP2 to PIP3, a molecule responsible for activation of other proteins playing a vital role in the axon growth.
The par 3/ par6 complex will also inhibit the GSK3β which is responsible for the inhibition of CRMP2, Tubulin, APC and microtubule associated proteins (MAPs).
Definitions
Axon Specification
In establishing a polarized neuron, the initial event is the specification of a single axon where one of the neurite will grow into a axon.
Axon Specification
In establishing a polarized neuron, the initial event is the specification of a single axon where one of the neurite will grow into a axon.
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