Karyopherin-mediated nuclear protein import

Signal-dependent import of a protein cargo from the cytosol into the nucleus through the nuclear pore complex, driven by the Ran GTPase gradient. A karyopherin carrier recognizes the cargo in the cytosol, either through an importin-alpha adaptor that binds a classical nuclear localization signal and bridges it to importin-beta1, or directly through an importin-beta-family carrier (importin-beta1, importin-7, importin-8). The carrier-cargo complex moves through the pore by transient contacts with FG-repeat nucleoporins. In the nucleus, RanGTP (kept high by the chromatin-bound exchange factor RCC1) binds the carrier and releases the cargo into the nucleoplasm. Carriers return to the cytosol, importin-alpha by the RanGTP-dependent exporter CSE1L, and cytosolic RanGAP1 with RanBP1 hydrolyses the exported RanGTP; NTF2 returns RanGDP to the nucleus. The module is cargo-neutral so that signalling modules can include it wherever a transcription factor activated in the cytosol must reach its nuclear targets (STATs, SMADs).

MODULE:karyopherin_nuclear_protein_importDRAFTABSTRACTBiological Processmodules/karyopherin_nuclear_protein_import.yaml
protein import into nucleusGO:0006606
PMID:17287812
Molecular mechanism of the nuclear protein import cycle.
Review of the karyopherin import cycle as a spatially organized cycle of cargo, carrier and Ran GTPase interactions.
The nuclear import of proteins through nuclear pore complexes (NPCs) illustrates how a complex biological function can be generated by a spatially and temporally organized cycle of interactions between cargoes, carriers and the Ran GTPase.
PMID:9323134
Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor.
Establishes the importin-alpha/beta route, RanGTP-driven release in the nucleus, CSE1L (CAS)-mediated return of importin-alpha, and its cytosolic release by RanBP1 and RanGAP1.
NLS proteins are transported into the nucleus by the importin alpha/beta heterodimer.

Written for reuse by module_ref from signalling modules, to make explicit the step that GO-CAM models leave implicit when a cytosolic kinase directly activates a transcription factor whose activity is placed in the nucleus (see projects/GOCAM_COMPARTMENTS.md). Which carrier route a cargo uses is a property of the cargo, recorded in the including module: STAT1 uses the importin-alpha5 (KPNA1) route and STAT3 importin-alpha3 (KPNA4); activated SMAD3 binds importin-beta1 directly, and activated SMADs are imported by importin-7/8. The nuclear pore itself is not re-modelled here; the translocation step names FG-nucleoporins only as the surface the carrier moves along. No member of this module has a gene review yet, so the annotons are grounded by UniProt accession and literature only.

8Nodes
5Parts
1Variant Sets
2Variants
10Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:karyopherin_nuclear_protein_import deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • cargo_recognition → pore_translocation [NOT_CHECKED]
  • pore_translocation → rangtp_cargo_release [NOT_CHECKED]
  • rangtp_cargo_release → carrier_recycling [NOT_CHECKED]
  • rangtp_cargo_release → importin_alpha_reexport [NOT_CHECKED]

Function consistency and core coverage

0 gene-function check(s) reflected in core functions · 0 conflict(s) · 16 evidence or coverage gap(s) (16 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
importin_alpha_adaptor KPNA1
UniProtKB:P52294
Family Representative 		nuclear import signal receptor activity
GO:0061608 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
importin_alpha_adaptor KPNA4
UniProtKB:O00629
Family Representative 		nuclear import signal receptor activity
GO:0061608 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
importin_alpha_adaptor KPNA2
UniProtKB:P52292
Family Representative 		nuclear import signal receptor activity
GO:0061608 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
importin_beta1_alpha_route KPNB1
UniProtKB:Q14974
Gene 		nuclear import signal receptor activity
GO:0061608 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
importin_beta_direct_carrier KPNB1
UniProtKB:Q14974
Family Representative 		nuclear import signal receptor activity
GO:0061608 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
importin_beta_direct_carrier IPO7
UniProtKB:O95373
Family Representative 		nuclear import signal receptor activity
GO:0061608 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
importin_beta_direct_carrier IPO8
UniProtKB:O15397
Family Representative 		nuclear import signal receptor activity
GO:0061608 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
fg_nucleoporin NUP153
UniProtKB:P49790
Family Representative 		structural constituent of nuclear pore
GO:0017056 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
ran_gtpase RAN
UniProtKB:P62826
Gene 		GTPase activity
GO:0003924 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rcc1_ran_gef RCC1
UniProtKB:P18754
Gene 		guanyl-nucleotide exchange factor activity
GO:0005085 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rangap1_cytosolic_gap RANGAP1
UniProtKB:P46060
Gene 		GTPase activator activity
GO:0005096 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
nutf2_rangdp_import NUTF2
UniProtKB:P61970
Gene 		nucleocytoplasmic carrier activity
GO:0140142 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
cse1l_importin_alpha_exporter CSE1L
UniProtKB:P55060
Gene 		nuclear export signal receptor activity
GO:0005049 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
importin_alpha_adaptor importin-alpha family
Family 		nuclear import signal receptor activity
GO:0061608 		Family Id Missing
The family has no identifier linking it to a curated family review.
importin_beta_direct_carrier importin-beta (karyopherin-beta) family carriers
Family 		nuclear import signal receptor activity
GO:0061608 		Family Id Missing
The family has no identifier linking it to a curated family review.
fg_nucleoporin FG-repeat nucleoporins
Family 		structural constituent of nuclear pore
GO:0017056 		Family Id Missing
The family has no identifier linking it to a curated family review.

Gene-review completeness (0/13 grounded genes reviewed)

0 complete review(s) · 0 with deep research · 13 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
KPNA4 O00629 ✗ — —
IPO8 O15397 ✗ — —
IPO7 O95373 ✗ — —
RCC1 P18754 ✗ — —
RANBP1 P43487 ✗ — —
RANGAP1 P46060 ✗ — —
NUP153 P49790 ✗ — —
KPNA2 P52292 ✗ — —
KPNA1 P52294 ✗ — —
CSE1L P55060 ✗ — —
NUTF2 P61970 ✗ — —
RAN P62826 ✗ — —
KPNB1 Q14974 ✗ — —

Details

Context
EukaryotaNCBITaxon:2759
cytosolGO:0005829 nuclear envelopeGO:0005635 nucleoplasmGO:0005654
Karyopherin-mediated nuclear protein importBiological Processkaryopherin_nuclear_protein_import
protein import into nucleusGO:0006606
Context
EukaryotaNCBITaxon:2759
cytosolGO:0005829 nuclear envelopeGO:0005635 nucleoplasmGO:0005654

Connections

The carrier-cargo complex formed in the cytosol enters the pore.
On reaching the nucleus the complex meets RanGTP, which releases the cargo.
The RanGTP-bound carrier returns to the cytosol, where RanGAP1 hydrolyses the GTP.
Released importin-alpha is exported by CSE1L with RanGTP.
NTF2 returns RanGDP to the nucleus, where RCC1 recharges it, sustaining the RanGTP gradient that drives release.
Part 1: cargo recognition by a karyopherin carrier in the cytosol
Cargo recognition by a karyopherin carrierTransport Stepcargo_recognition

The cargo is bound in the cytosol by an import carrier, either via an importin-alpha adaptor and importin-beta1, or directly by an importin-beta-family carrier. Which route is used depends on the cargo.

Variant set: Carrier route by how the cargo is recognized by the import carrier (One Or More)
Importin-alpha/importin-beta1 routeTransport Stepimportin_alpha_beta_route

An importin-alpha adaptor binds the cargo's nuclear localization signal and importin-beta1, which carries the trimeric complex through the pore. Used by tyrosine-phosphorylated STAT1 (importin-alpha5/KPNA1) and STAT3 (importin-alpha3/KPNA4).

Annotons

Importin-alpha cargo adaptor
importin_alpha_adaptor
Participant: Family: importin-alpha family
Family:
importin-alpha family Armadillo-repeat adaptors that bind classical nuclear localization signals and importin-beta1. No PANTHER id is asserted; the family is identified by its members. Members differ in cargo: KPNA2 (Rch1) is a general cNLS adaptor but does not import STAT1, which uses KPNA1 (NPI-1).
Representative Members: KPNA1UniProtKB:P52294 KPNA4UniProtKB:O00629 KPNA2UniProtKB:P52292

Function

nuclear import signal receptor activityGO:0061608

Processes

protein import into nucleusGO:0006606

Locations

cytosolGO:0005829

Recognizes the cargo's nuclear localization signal and links it to importin-beta1.

PMID:9384585
Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1.
Tyrosine-phosphorylated STAT1 is imported by importin-beta1 through the NPI-1 (importin-alpha5) adaptor family.
Tyrosine-phosphorylated Stat1 associated with the beta subunit (a 97 kDa component) of the nuclear pore-targeting complex via the NPI-1 family, but not the Rch1 family, of alpha subunit
PMID:15919823
STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3.
STAT3 is recognized by importin-alpha3 through a coiled-coil region.
this region is critical for its recognition by specific import carrier importin-alpha3
Importin-beta1 carrier (with importin-alpha)
importin_beta1_alpha_route
Participant: Gene Product: KPNB1
Gene Product:
KPNB1UniProtKB:Q14974

Function

nuclear import signal receptor activityGO:0061608

Processes

protein import into nucleusGO:0006606

Locations

cytosolGO:0005829

Binds the importin-alpha/cargo complex and mediates its translocation through the pore.

PMID:9323134
Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor.
Importin-alpha binds the NLS while importin-beta mediates translocation.
Importin alpha binds the NLS, while importin beta mediates translocation through the nuclear pore complex.
Direct importin-beta-family routeTransport Stepdirect_importin_beta_route

An importin-beta-family carrier binds the cargo without an importin-alpha adaptor. Receptor-activated SMAD3 binds importin-beta1 through its N-terminal domain, and activated SMAD1 and SMAD2/3 are imported by importin-7 and importin-8.

Annotons

Importin-beta-family direct carrier
importin_beta_direct_carrier
Participant: Family: importin-beta (karyopherin-beta) family carriers
Family:
importin-beta (karyopherin-beta) family carriers HEAT-repeat Ran-binding carriers that bind cargo directly. No PANTHER id is asserted; the family is identified by its members.
Representative Members: KPNB1UniProtKB:Q14974 IPO7UniProtKB:O95373 IPO8UniProtKB:O15397

Function

nuclear import signal receptor activityGO:0061608

Processes

protein import into nucleusGO:0006606

Locations

cytosolGO:0005829

Binds the cargo directly and carries it through the pore.

PMID:11294908
Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner.
Receptor-activated SMAD3 binds importin-beta1 directly; importin-beta1, Ran and NTF2 suffice for its import.
Importin-beta1, Ran, and p10/NTF2 are sufficient to mediate import of activated Smad3.
PMID:17785517
Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads.
Importin-7 and importin-8 are required for nuclear accumulation of BMP-activated SMAD1 and TGF-beta-activated SMAD2/3.
knockdown of importin 7 and 8 (Imp7 and 8), the mammalian orthologues of Msk, markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-beta.
Part 2: translocation through the nuclear pore
Translocation through the nuclear poreTransport Steppore_translocation

The carrier-cargo complex passes through the central channel of the nuclear pore complex by transient contacts with FG-repeat nucleoporins. NUP153, on the nuclear basket, is named as a representative FG-nucleoporin; the pore complex as a whole is not modelled here.

Annotons

FG-repeat nucleoporin
fg_nucleoporin
Participant: Family: FG-repeat nucleoporins
Family:
FG-repeat nucleoporins Nucleoporins whose FG repeats form the permeability barrier that karyopherins traverse.
Representative Members: NUP153UniProtKB:P49790

Function

structural constituent of nuclear poreGO:0017056

Locations

nuclear envelopeGO:0005635

Provides the FG-repeat surface along which the carrier-cargo complex moves.

Part 3: RanGTP-dependent cargo release in the nucleus
RanGTP-dependent cargo releaseTransport Steprangtp_cargo_release

Nuclear RanGTP binds importin-beta and releases the cargo (and importin-alpha) into the nucleoplasm. RCC1, bound to chromatin, charges Ran with GTP and so keeps RanGTP high in the nucleus.

Annotons

Ran GTPase
ran_gtpase
Participant: Gene Product: RAN
Gene Product:
RANUniProtKB:P62826

Function

GTPase activityGO:0003924

Processes

protein import into nucleusGO:0006606

Locations

nucleoplasmGO:0005654

In its GTP-bound form binds importin-beta in the nucleus and displaces the cargo.

PMID:9323134
Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor.
Nuclear RanGTP binds importin-beta and displaces importin-alpha with its cargo.
RanGTP, whose predicted concentration is high in the nucleus and low in the cytoplasm, binds importin beta and displaces importin alpha.
PMID:11294908
Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner.
Ran releases activated SMAD3 from importin-beta1.
Nuclear import of Smad3 in vivo requires the action of the Ran GTPase, which mediates release of Smad3 from the complex with importin-beta1.
RCC1 Ran guanine-nucleotide exchange factor
rcc1_ran_gef
Participant: Gene Product: RCC1
Gene Product:
RCC1UniProtKB:P18754

Function

guanyl-nucleotide exchange factor activityGO:0005085

Locations

nucleoplasmGO:0005654

Chromatin-bound exchange factor that loads Ran with GTP, maintaining the nuclear RanGTP pool.

PMID:1944575
Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1.
RCC1 is a nuclear, chromatin-bound protein that catalyses guanine nucleotide exchange on Ran.
Here we show that RCC1 specifically catalyses the exchange of guanine nucleotides on the Ran protein
Part 4: carrier return and Ran gradient maintenance
Carrier return and Ran gradient maintenanceTransport Stepcarrier_recycling

Carriers return to the cytosol for another round. Importin-alpha is exported by CSE1L in a complex with RanGTP; in the cytosol RanBP1 and RanGAP1 release it and convert RanGTP to RanGDP, which NTF2 carries back into the nucleus.

Annotons

RanGAP1 cytosolic Ran GTPase-activating protein
rangap1_cytosolic_gap
Participant: Gene Product: RANGAP1
Gene Product:
RANGAP1UniProtKB:P46060

Function

GTPase activator activityGO:0005096

Locations

cytosolGO:0005829

Stimulates GTP hydrolysis on exported Ran, keeping cytosolic RanGTP low.

PMID:9323134
Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor.
RanBP1 and RanGAP1 release importin-alpha from the CSE1L/RanGTP export complex in the cytosol.
Importin alpha is released from this complex in the cytoplasm by the combined action of RanBP1 and RanGAP1.
RanBP1 cofactor of RanGAP1
ranbp1_ran_binding_cofactor
Participant: Gene Product: RANBP1
Gene Product:
RANBP1UniProtKB:P43487

Locations

cytosolGO:0005829

Acts with RanGAP1 in the cytosol to release importin-alpha from the CSE1L/RanGTP export complex and allow GTP hydrolysis on Ran.

PMID:9323134
Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor.
RanBP1 and RanGAP1 together release importin-alpha from the export complex in the cytoplasm.
Importin alpha is released from this complex in the cytoplasm by the combined action of RanBP1 and RanGAP1.
NTF2 RanGDP import carrier
nutf2_rangdp_import
Participant: Gene Product: NUTF2
Gene Product:
NUTF2UniProtKB:P61970

Function

nucleocytoplasmic carrier activityGO:0140142

Locations

cytosolGO:0005829

Binds RanGDP in the cytosol and returns it to the nucleus, where RCC1 recharges it.

PMID:11294908
Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner.
NTF2 is one of the minimal factors needed to reconstitute import of activated SMAD3.
Importin-beta1, Ran, and p10/NTF2 are sufficient to mediate import of activated Smad3.
Part 5: importin-alpha re-export (optional)

Needed only for the importin-alpha/beta route; cargoes carried directly by an importin-beta-family carrier do not use it.

Importin-alpha re-export by CSE1LTransport Stepimportin_alpha_reexport

CSE1L binds cargo-free importin-alpha together with RanGTP and exports it to the cytosol.

Annotons

CSE1L importin-alpha exporter
cse1l_importin_alpha_exporter
Participant: Gene Product: CSE1L
Gene Product:
CSE1LUniProtKB:P55060

Function

nuclear export signal receptor activityGO:0005049

Processes

protein export from nucleusGO:0006611

Locations

nucleoplasmGO:0005654

Binds cargo-free importin-alpha with RanGTP in the nucleus and returns it to the cytosol, leaving the cargo behind.

PMID:9323134
Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor.
CSE1L (CAS) mediates RanGTP-dependent re-export of cargo-free importin-alpha.
CAS binds strongly to importin alpha only in the presence of RanGTP, forming an importin alpha/CAS/RanGTP complex.