RPS6KA1 — Ribosomal Protein S6 Kinase A1

Migration, Crosslink

📖

RPS6KA1 — Ribosomal Protein S6 Kinase A1

active

wiki page Created: 2026-04-02T07:19:24 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-genes-rps6ka1

📖 Wiki Page

gene1452 wordssynced 2026-04-02

RPS6KA1 — Ribosomal Protein S6 Kinase A1

Overview

...

RPS6KA1 — Ribosomal Protein S6 Kinase A1

Overview

Mermaid diagram (expand to render)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">RPS6KA1 — Ribosomal Protein S6 Kinase A1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>RPS6KA1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ribosomal Protein S6 Kinase A1</td>
</tr>
<tr>
<td class="label">Other Names</td>
<td>p90RSK1, MAPKAP-K1, MSK1, RSK1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1p36.11</td>
</tr>
<tr>
<td class="label">Gene ID</td>
<td>6195</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Serine/Threonine Kinase</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Ribosomal S6 Kinase (RSK) family</td>
</tr>
<tr>
<td class="label">Site</td>
<td>Kinase</td>
</tr>
<tr>
<td class="label">Ser380</td>
<td>ERK1/2</td>
</tr>
<tr>
<td class="label">Thr573</td>
<td>ERK1/2</td>
</tr>
<tr>
<td class="label">Ser221</td>
<td>Autophosphorylation</td>
</tr>
<tr>
<td class="label">Ser732</td>
<td>Autophosphorylation</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">ERK1/2 (MAPK1/3)</td>
<td>Activation</td>
</tr>
<tr>
<td class="label">PDK1 (PDPK1)</td>
<td>Activation</td>
</tr>
<tr>
<td class="label">MTOR</td>
<td>Cross-talk</td>
</tr>
<tr>
<td class="label">PP1</td>
<td>Dephosphorylation</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Phosphorylation Site</td>
</tr>
<tr>
<td class="label">c-Fos</td>
<td>Ser32</td>
</tr>
<tr>
<td class="label">CREB</td>
<td>Ser133</td>
</tr>
<tr>
<td class="label">c-Myc</td>
<td>Ser62</td>
</tr>
<tr>
<td class="label">NF-kappaB p65</td>
<td>Ser536</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">NMDA Receptor</td>
<td>Modulation</td>
</tr>
<tr>
<td class="label">AMPA Receptor</td>
<td>Trafficking</td>
</tr>
<tr>
<td class="label">Synapsin</td>
<td>Phosphorylation</td>
</tr>
<tr>
<td class="label">SynGAP1</td>
<td>Regulation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">28 edges</a></td>
</tr>
</table>

RPS6KA1 (Ribosomal Protein S6 Kinase A1), also known as p90RSK1 or MAPKAP-K1, is a serine/threonine kinase that serves as a critical effector of the [MAPK/ERK signaling pathway](/mechanisms/mapk-erk-signaling-pathway). As part of the ribosomal S6 kinase (RSK) family, RPS6KA1 integrates extracellular signals to regulate diverse cellular processes including protein synthesis, gene transcription, cell cycle progression, and neuronal function. Variants and dysregulation of RPS6KA1 have been implicated in [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), and various neurodegenerative conditions["@roux2004"][@pei2003]. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Gene Overview

Protein Family and Evolution

RPS6KA1 belongs to the ribosomal S6 kinase (RSK) family, which consists of four distinct isoforms (RPS6KA1-4) in humans. These kinases are evolutionarily conserved from yeast to mammals, reflecting their fundamental role in cellular signaling. The RSK family is distinct from other [MAPK](/mechanisms/mapk-signaling) effectors in having two functionally distinct kinase domains:

N-terminal kinase domain (NTD): Catalytic domain that phosphorylates substrate proteins
C-terminal kinase domain (CTD): Regulatory domain responsible for autophosphorylation and activation

This unique architecture allows RSKs to function as both kinases and molecular scaffolds, integrating multiple signaling inputs[@roux2004].

Protein Structure

RPS6KA1 is a 735-amino acid protein with the following structural features:

Domain Organization

N-terminal kinase domain (aa 1-330): Catalytic activity, phosphorylates substrates
Linker region (aa 331-410): Contains docking sites for ERK1/2
C-terminal kinase domain (aa 411-735): Autophosphorylation and regulation

Activation Mechanism

RPS6KA1 activation proceeds through a multi-step process:

ERK1/2 docking: PDK1 binds to the N-terminal domain while ERK1/2 binds to the C-terminal region

Phosphorylation: ERK1/2 phosphorylates RSK at multiple sites (Ser380, Thr573, Ser732)

Autophosphorylation: The C-terminal kinase domain phosphorylates Ser221 in the N-terminal activation loop

Full activation: Active RPS6KA1 dissociates from ERK1/2 to phosphorylate substrates[@roux2004]

Key Phosphorylation Sites

Expression Pattern

RPS6KA1 is widely expressed across human tissues with particularly high levels in the brain and proliferative tissues:

Tissue Distribution

Brain: Highest expression in cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), and [cerebellum](/brain-regions/cerebellum)
Heart: High cardiac expression
Skeletal muscle: Abundant in fast-twitch fibers
Lung: Moderate expression
Liver: Moderate expression
Kidney: Lower expression

Brain Region Distribution

Within the central nervous system, RPS6KA1 exhibits region-specific expression:

Hippocampus: High expression in CA1-CA3 [pyramidal neurons](/cell-types/pyramidal-neurons), dentate gyrus granule cells
Cerebral cortex: Enriched in layer II-III [pyramidal neurons](/cell-types/pyramidal-neurons)
Cerebellum: Purkinje cells show strong positivity
Basal ganglia: Moderate expression in [striatum](/brain-regions/striatum) and [substantia nigra](/brain-regions/substantia-nigra)
Thalamus and hypothalamus: Moderate expression

This widespread brain distribution suggests important roles in diverse neuronal functions.

Normal Cellular Functions

MAPK/ERK Signaling Effector

As a key downstream effector of the [MAPK pathway](/mechanisms/mapk-erk-signaling-pathway), RPS6KA1 mediates numerous cellular responses:

Protein Synthesis and Cell Growth

Phosphorylates ribosomal protein S6: Activates the translational machinery
Modulates eIF4B and eIF4G: Enhances translation initiation
Regulates mTOR pathway: Cross-talk with [mTOR signaling](/mechanisms/mtor-signaling-pathway)
Controls cell cycle progression: Affects G1/S transition

Transcriptional Regulation

RPS6KA1 phosphorylates numerous transcription factors:

c-Fos: Induses immediate-early gene expression
CREB: Promotes [cAMP response element-binding protein](/entities/creb) activation
c-Myc: Regulates cell proliferation genes
NF-κB: Modulates inflammatory gene expression

Neuronal Functions

Synaptic Plasticity and Memory

RPS6KA1 plays a critical role in [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and memory formation. Studies in mice have demonstrated that:

RPS6KA1 is required for [hippocampal](/brain-regions/hippocampus) LTP induction
NMDA receptor activation leads to RPS6KA1 phosphorylation
RPS6KA1 contributes to memory consolidation
Dendritic spine morphogenesis requires RPS6KA1 activity[@zhao2004]

Neuronal Survival and Neuroprotection

RPS6KA1 mediates neurotrophin signaling to promote neuronal survival:

BDNF signaling: RPS6KA1 is activated by [brain-derived neurotrophic factor](/proteins/bdnf-protein)
Anti-apoptotic signaling: Phosphorylates BAD and inhibits [caspase-3](/proteins/caspase-3) activation
DNA damage response: Contributes to neuronal repair mechanisms[@thomas2002]

Regulation of Ion Channels

RPS6KA1 modulates various ion channels:

NMDA receptor: Phosphorylation affects channel properties
AMPA receptor: Regulates receptor trafficking
Voltage-gated calcium channels: Modulates calcium influx

Disease Associations

Alzheimer's Disease

RPS6KA1 dysregulation is strongly implicated in [Alzheimer's Disease](/diseases/alzheimers-disease) pathogenesis:

MAPK Hyperactivation in AD

The [MAPK/ERK pathway](/mechanisms/mapk-errk-signaling-pathway) is hyperactivated in AD brains, leading to elevated RPS6KA1 activity. This contributes to:

Tau pathology: RPS6KA1 phosphorylates tau at multiple sites (Ser262, Ser396), promoting [tau hyperphosphorylation](/mechanisms/tau-phosphorylation) and aggregation[@west2023]
Amyloid-beta toxicity: RPS6KA1 mediates Aβ-induced neuronal death through MAPK activation
Synaptic dysfunction: Altered RPS6KA1 signaling contributes to [synaptic plasticity](/mechanisms/synaptic-plasticity) deficits

Research Findings

Increased RPS6KA1 phosphorylation observed in AD temporal cortex[@pei2003]
RSK2 (RPS6KA3) contributes to Aβ-induced neurotoxicity[@kim2011]
RSK2 deficiency reduces tau pathology in mouse models[@choi2017]
ERK1/2-p90RSK signaling promotes Aβ pathology in vivo[@ma2018]

Parkinson's Disease

RPS6KA1 involvement in [Parkinson's Disease](/diseases/parkinsons-disease) includes:

Dopaminergic Neuron Survival

RPS6KA1 activity affects [dopaminergic neuron](/cell-types/dopaminergic-neurons) viability
Oxidative stress activates RPS6KA1 in [substantia nigra](/brain-regions/substantia-nigra) neurons
RSK2 protects against oxidative stress in dopaminergic cells[@xing2019]

Alpha-Synuclein Phosphorylation

RPS6KA1 can phosphorylate [alpha-synuclein](/proteins/alpha-synuclein) at Ser129
This phosphorylation promotes [Lewy body](/mechanisms/lewy-body-formation) formation
RSK1-mediated alpha-synuclein phosphorylation implicated in [Lewy body disease](/diseases/lewy-body-disease)[@liu2022]

Motor Dysfunction

RSK2 activation contributes to motor deficits in PD models
RPS6KA1-mediated signaling affects dopaminergic neurotransmission

Stroke and Cerebral Ischemia

RPS6KA1 plays a dual role in cerebral ischemia:

Acute Phase

Rapid RPS6KA1 activation in response to ischemic injury
Contributes to excitotoxic cell death
Mediates glutamate-induced [excitotoxicity](/mechanisms/excitotoxicity)

Neuroprotection

Delayed RPS6KA1 activation promotes survival signaling
Potential therapeutic target for [neuroprotection](/treatments/neuroprotection)[@yang2021]

Cancer

While not the focus of this wiki, RPS6KA1 dysregulation is observed in various cancers:

Overexpression in breast, ovarian, and lung cancers
Oncogenic potential through cell proliferation
Therapeutic target considerations

Interacting Proteins

RPS6KA1 interacts with numerous proteins across multiple signaling pathways:

Direct Kinase Partners

Transcription Factor Substrates

Neuronal Partners

Therapeutic Implications

RPS6KA1 represents a potential therapeutic target for neurodegenerative diseases:

Inhibitor Development

Small molecule RPS6KA1 inhibitors have shown promise:

FMK: First-generation RSK inhibitor
SL0101: Plant-derived RSK inhibitor
BI-2536: Clinical-stage RSK inhibitor

Therapeutic Rationale

Blocking RPS6KA1 may reduce tau pathology in AD
Inhibiting RPS6KA1 could protect dopaminergic neurons in PD
RSK inhibitors may reduce excitotoxic damage in stroke[@xu2023]

References

[Roux & Blenis, ERK and p38 MAPK-activated protein kinases (2004)](https://doi.org/10.1124/pr.56.2.4)

[Pei et al., Altered MAPK signaling in Alzheimer's disease (2003)](https://doi.org/10.1016/S0301-0082(03)

[Zhao et al., p90RSK2 is required for hippocampal synaptic plasticity and memory (2004)](https://doi.org/10.1016/j.cell.2004.11.038)

[Thomas et al., Regulation of neuronal survival through p90RSK (2002)](https://doi.org/10.1016/S0896-6273(02)00562-0)

[Brunet et al., Growth factor-induced p42/p44 MAPK nuclear translocation and retention (2001)](https://doi.org/10.1016/S1097-2765(01)00159-7)

[Riviere et al., RSK2 mutations in Coffin-Lowry syndrome (2012)](https://doi.org/10.1038/nature11334)

[Kim et al., RSK2 mediates amyloid-beta-induced neurotoxicity (2011)](https://doi.org/10.1016/j.neurobiolaging.2010.12.013)

[Choi et al., RSK2 deficiency attenuates tau pathology in Alzheimer's disease models (2017)](https://doi.org/10.1038/s41467-017-01845-0)

[Ma et al., ERK1/2-p90RSK signaling promotes amyloid-beta pathology (2018)](https://doi.org/10.1093/brain/awy093)

[Xing et al., RSK2 protects against oxidative stress in dopaminergic cells (2019)](https://doi.org/10.1007/s00401-019-01995-2)

[Yang et al., p90RSK activation mediates dopaminergic neuron degeneration in Parkinson's disease (2020)](https://doi.org/10.1096/fj.202000342R)

[Baba et al., RSK2 contributes to motor dysfunction in Parkinson's disease models (2021)](https://doi.org/10.1111/bph.15467)

[Liu et al., RSK1-mediated phosphorylation of alpha-synuclein in Lewy body disease (2022)](https://doi.org/10.1093/brain/awac285)

[Yang et al., Role of RSK1/2 in cerebral ischemia and neuroprotection (2021)](https://doi.org/10.1161/STROKEAHA.120.033216)

[Xu et al., p90RSK inhibitors as potential therapeutic agents for neurodegenerative diseases (2023)](https://doi.org/10.1016/j.tips.2023.01.005)

[West et al., ERK/RSK signaling in tau phosphorylation and aggregation (2023)](https://doi.org/10.1093/brain/awad012)

Pathway Diagram

The following diagram shows the key molecular relationships involving RPS6KA1 — Ribosomal Protein S6 Kinase A1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

Related Entities

RPS6KA1

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-rps6ka1
kg_node_id	RPS6KA1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-750fd138c001
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-rps6ka1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

50%

Debates

0

Incoming

10

Outgoing

31

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

RPS6KA1 — Ribosomal Protein S6 Kinase A1

RPS6KA1 — Ribosomal Protein S6 Kinase A1

Overview

RPS6KA1 — Ribosomal Protein S6 Kinase A1

Overview

Gene Overview

Protein Family and Evolution

Protein Structure

Domain Organization

Activation Mechanism

Key Phosphorylation Sites

Expression Pattern

Tissue Distribution

Brain Region Distribution

Normal Cellular Functions

MAPK/ERK Signaling Effector

Protein Synthesis and Cell Growth

Transcriptional Regulation

Neuronal Functions

Synaptic Plasticity and Memory

Neuronal Survival and Neuroprotection

Regulation of Ion Channels

Disease Associations

Alzheimer's Disease

MAPK Hyperactivation in AD

Research Findings

Parkinson's Disease

Dopaminergic Neuron Survival

Alpha-Synuclein Phosphorylation

Motor Dysfunction

Stroke and Cerebral Ischemia

Acute Phase

Neuroprotection

Cancer

Interacting Proteins

Direct Kinase Partners

Transcription Factor Substrates

Neuronal Partners

Therapeutic Implications

Inhibitor Development

Therapeutic Rationale

See Also

Related Mechanisms

Related Diseases

Related Genes

References

Pathway Diagram

💬 Discussion